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<p class="text-center font-size-24"> | <p class="text-center font-size-24"> | ||
</p><h1 class="banner-h1">Machine Learning</h1> | </p><h1 class="banner-h1">Machine Learning</h1> | ||
− | <h2 class="banner-h2">Results</h2> | + | <h2 class="banner-h2">Results</h2><br/> |
<div class="banner-overlay"></div> | <div class="banner-overlay"></div> | ||
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the data of 1360 A. <em>baumannii</em> strains along with 10 different antibiotics. | the data of 1360 A. <em>baumannii</em> strains along with 10 different antibiotics. | ||
</p> | </p> | ||
+ | <br/><br/><br/> | ||
<!--- <Graph representing the distribution of strains></Graph> --> | <!--- <Graph representing the distribution of strains></Graph> --> | ||
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/3/3a/T--IIT_Roorkee--images--images--ML_Results_table_strains.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/3/3a/T--IIT_Roorkee--images--images--ML_Results_table_strains.png"/> | ||
− | </div> | + | </div><br/><br/> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/1/1b/T--IIT_Roorkee--images--images--ML_Results_distribution_strains.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/1/1b/T--IIT_Roorkee--images--images--ML_Results_distribution_strains.png"/> | ||
− | </div> | + | </div><br/><br/> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
The results of machine learning can be summarized in the following two points | The results of machine learning can be summarized in the following two points | ||
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</ol> | </ol> | ||
<p></p> | <p></p> | ||
+ | |||
+ | <br/><br/><br/><br/> | ||
+ | |||
<h2 class="wiki-h wiki-h2 wiki-section-start" id="wiki_section_1"> | <h2 class="wiki-h wiki-h2 wiki-section-start" id="wiki_section_1"> | ||
+ | |||
Detection of Genes conferring Antibiotic resistance | Detection of Genes conferring Antibiotic resistance | ||
− | </h2> | + | </h2><br/> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
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</button> | </button> | ||
<div class="wiki-collapsed-content"> | <div class="wiki-collapsed-content"> | ||
− | < | + | |
− | < | + | |
+ | |||
+ | |||
+ | |||
+ | |||
+ | <table class="table table-hover table-bordered side-wrapped-item"> | ||
+ | <thead class="thead-dark"> | ||
+ | <tr> | ||
+ | <th scope="col">Genes</th> | ||
+ | <th scope="col">Antibiotic</th> | ||
+ | <th scope="col">Gene Ontology<br/> Annotations</th> | ||
+ | <th scope="col">Mechanism of Action</th> | ||
+ | <th scope="col">References</th> | ||
+ | </tr> | ||
+ | </thead> | ||
+ | <tbody> | ||
+ | <tr> | ||
+ | <td><i>esiB</i></td> | ||
+ | <td>iprofloxacin Levofloxacin</td> | ||
+ | <td>GO_esiB</td> | ||
+ | <td>Secretory immunoglobulin <br/>A-binding protein</td> | ||
+ | <td>Ref1_esiB</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>aroP</i></td> | ||
+ | <td>iprofloxacin Levofloxacin</td> | ||
+ | <td>GO_aroP</td> | ||
+ | <td>Aromatic amino acid <br/>transport protein</td> | ||
+ | <td>-</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>tnsB</i></td> | ||
+ | <td>Ciprofloxacin</td> | ||
+ | <td>GO_tnsB</td> | ||
+ | <td>Transposon Tn7 transposition protein</td> | ||
+ | <td>Ref1_tnsB</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>xerC</i></td> | ||
+ | <td>Ciprofloxacin</td> | ||
+ | <td>GO_xerC</td> | ||
+ | <td>Tyrosine recombinase</td> | ||
+ | <td>Ref1_xerC, Ref2_xerC</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>asnC</i></td> | ||
+ | <td>Levofloxacin</td> | ||
+ | <td>GO_asnC</td> | ||
+ | <td>Regulatory protein, AsnC</td> | ||
+ | <td>-</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>puuP</i></td> | ||
+ | <td>Levofloxacin</td> | ||
+ | <td>GO_puup</td> | ||
+ | <td>Putrescine importer</td> | ||
+ | <td>Ref1_puuP, Ref2_puuP</td> | ||
+ | </tr> | ||
+ | </tbody> | ||
+ | </table> | ||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>esiB</b> </i>(Ciprofloxacin and Levofloxacin)</h4> | ||
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | esiB encodes for Secretory immunoglobulin A-binding protein (UP_esiB). | + | <i>esiB </i>encodes for Secretory immunoglobulin A-binding protein (UP_esiB). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: IgA binding and Metal ion binding | + | <b>GO Molecular function</b>: IgA binding and Metal ion binding |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Negative regulation of immune response and neutrophil activation, and pathogenesis | + | <b>GO Biological function</b>: Negative regulation of immune response and neutrophil activation, and pathogenesis |
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_esiB | + | <b>Complete GO annotation</b>: GO_esiB |
<br/><br/> | <br/><br/> | ||
− | According to the study of Pastorello et al. (Ref1_esiB), they concluded that esiB helps in secretion of the | + | According to the study of Pastorello <i>et al.</i> (Ref1_esiB), they concluded that <i>esiB </i>helps in secretion of the |
protein which binds with immunoglobulins in the blood or antibodies helping bacteria escape from neutrophil | protein which binds with immunoglobulins in the blood or antibodies helping bacteria escape from neutrophil | ||
(cell eating bacteria). The neutrophil is the most common White Blood Cells (WBC) in the human body, so these | (cell eating bacteria). The neutrophil is the most common White Blood Cells (WBC) in the human body, so these | ||
proteins help the bacterial pathogen in escaping the immune system pathway in the patients of Urinary Tract | proteins help the bacterial pathogen in escaping the immune system pathway in the patients of Urinary Tract | ||
− | Infections. The study also concluded that esiB is preferentially associated with extraintestinal strains, | + | Infections. The study also concluded that <i>esiB </i>is preferentially associated with extraintestinal strains, |
while the gene is rarely found in either intestinal or nonpathogenic strains. | while the gene is rarely found in either intestinal or nonpathogenic strains. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: The presence and importance of this gene in the case of patients with Urinary Tract Infection (one | + | <b>Importance:</b> The presence and importance of this gene in the case of patients with Urinary Tract Infection (one |
of the major Hospital Acquired Infections) make it an important target/gene to explore using wet-lab | of the major Hospital Acquired Infections) make it an important target/gene to explore using wet-lab | ||
− | experiments in the case of A. baumannii. | + | experiments in the case of <i>A. baumannii</i>. |
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i>aroP<b></b> </i>(Ciprofloxacin and Levofloxacin)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | aroP encodes for Aromatic amino acid transport protein. It is a permease that is involved in the transport | + | <i>aroP </i>encodes for Aromatic amino acid transport protein. It is a permease that is involved in the transport |
across the cytoplasmic membrane of the aromatic amino acids (phenylalanine, tyrosine, and tryptophan), | across the cytoplasmic membrane of the aromatic amino acids (phenylalanine, tyrosine, and tryptophan), | ||
(UP_aroP). | (UP_aroP). | ||
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Transmembrane transporter activity of aromatic amino acids | + | <b>GO Molecular function</b>: Transmembrane transporter activity of aromatic amino acids |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Amino acids transport | + | <b>GO Biological function</b>: Amino acids transport |
<br/><br/> | <br/><br/> | ||
GO Cellular Component: Integral component of Plasma membrane | GO Cellular Component: Integral component of Plasma membrane | ||
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_aroP | + | <b>Complete GO annotation</b>: GO_aroP |
<br/><br/> | <br/><br/> | ||
− | Since aroP helps in encoding protein responsible for transportation aromatic amino acids, therefore it is | + | Since <i>aroP </i>helps in encoding protein responsible for transportation aromatic amino acids, therefore it is |
related to very basic cellular functions. Amino acids are important for the process of transcription and | related to very basic cellular functions. Amino acids are important for the process of transcription and | ||
translation, their transportation plays an important role in these functions. | translation, their transportation plays an important role in these functions. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: There is a lack of studies conducted for exploring the functioning of aroP in the context of A. | + | <b>Importance:</b> There is a lack of studies conducted for exploring the functioning of <i>aroP </i>in the context of A. |
baumannii (UP2_aroP), which makes it a novel and important target pathway to be explored for using wet-lab | baumannii (UP2_aroP), which makes it a novel and important target pathway to be explored for using wet-lab | ||
experiments, especially because it is involved in the basic cellular process i.e. amino acid transport. | experiments, especially because it is involved in the basic cellular process i.e. amino acid transport. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>tnsB</b>tnsB </i>(Ciprofloxacin)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | tnsB encodes for Transposon Tn7 transposition protein, which are very special proteins helping in cutting, | + | <i>tnsB </i>encodes for Transposon Tn7 transposition protein, which are very special proteins helping in cutting, |
pasting, and making copies of DNA in the chromosome (UP_tnsB). | pasting, and making copies of DNA in the chromosome (UP_tnsB). | ||
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: DNA Binding, and Transposase activity | + | <b>GO Molecular function</b>: DNA Binding, and Transposase activity |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: DNA Integration and DNA-mediated transposition | + | <b>GO Biological function</b>: DNA Integration and DNA-mediated transposition |
<br/><br/> | <br/><br/> | ||
GO Cellular Component: Cytoplasmic membrane | GO Cellular Component: Cytoplasmic membrane | ||
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_tnsB | + | <b>Complete GO annotation</b>: GO_tnsB |
<br/><br/> | <br/><br/> | ||
Ciprofloxacin acts by inhibition of DNA replication by inhibiting bacterial DNA topoisomerase and DNA-gyrase. | Ciprofloxacin acts by inhibition of DNA replication by inhibiting bacterial DNA topoisomerase and DNA-gyrase. | ||
Transposons help in DNA strand breakage which is also carried out by topoisomerase. These facts make it very | Transposons help in DNA strand breakage which is also carried out by topoisomerase. These facts make it very | ||
− | clear that tnsB is an important gene and target in the context of DNA replication and is involved in a similar | + | clear that <i>tnsB </i>is an important gene and target in the context of DNA replication and is involved in a similar |
mechanism as that of Ciprofloxacin. | mechanism as that of Ciprofloxacin. | ||
<br/><br/> | <br/><br/> | ||
− | Tn7 class transposon proteins are associated with carbapenem-resistance in A. baumannii (Ref1_tnsB). The study | + | Tn7 class transposon proteins are associated with carbapenem-resistance in <i>A. baumannii</i> (Ref1_tnsB). The study |
− | by Rose (Ref2_tnsB), discovered a novel Tn7-related transposon, | + | by Rose (Ref2_tnsB), discovered a novel Tn7-related transposon, Tn<i>AbaR1</i> which contributes to the accumulation |
and dissemination of antibiotic resistance genes. According to their study, Tn7 is a well-studied, highly | and dissemination of antibiotic resistance genes. According to their study, Tn7 is a well-studied, highly | ||
promiscuous cut-and-paste transposon, found in a variety of bacteria and mainly important for resistance to | promiscuous cut-and-paste transposon, found in a variety of bacteria and mainly important for resistance to | ||
antibiotics such as trimethoprim and streptomycin. | antibiotics such as trimethoprim and streptomycin. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: The involvement of tnsB in being a cause of resistance to several antibiotics makes it an | + | <b>Importance:</b> The involvement of <i>tnsB </i>in being a cause of resistance to several antibiotics makes it an |
important target and pathway to be explored especially in the context of our novel protein-based therapeutic | important target and pathway to be explored especially in the context of our novel protein-based therapeutic | ||
− | and our pathogen of interest, A. baumannii. | + | and our pathogen of interest, <i>A. baumannii</i>. |
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>xerC</b> </i>(Ciprofloxacin) </h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | xerC encodes for tyrosine recombinase, which acts by catalyzing the cutting and rejoining of the recombining | + | <i>xerC </i>encodes for tyrosine recombinase, which acts by catalyzing the cutting and rejoining of the recombining |
DNA molecules. | DNA molecules. | ||
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: DNA binding, Site-specific recombinase activity | + | <b>GO Molecular function</b>: DNA binding, Site-specific recombinase activity |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Cell cycle, Cell division, and Chromosome segregation | + | <b>GO Biological function</b>: Cell cycle, Cell division, and Chromosome segregation |
<br/><br/> | <br/><br/> | ||
GO Cellular Component: Cytoplasm | GO Cellular Component: Cytoplasm | ||
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_xerC | + | <b>Complete GO annotation</b>: GO_xerC |
<br/><br/> | <br/><br/> | ||
It binds cooperatively to specific DNA consensus sequences that are separated from XerD binding sites by a | It binds cooperatively to specific DNA consensus sequences that are separated from XerD binding sites by a | ||
Line 272: | Line 346: | ||
that specific pairs of active sites are sequentially switched on and off in the recombinase tetramer to ensure | that specific pairs of active sites are sequentially switched on and off in the recombinase tetramer to ensure | ||
that appropriate DNA strands will be exchanged at both reaction steps. These findings have been made for E. | that appropriate DNA strands will be exchanged at both reaction steps. These findings have been made for E. | ||
− | coli and it would be interesting to check for the same in the case of A. baumannii. | + | coli and it would be interesting to check for the same in the case of <i>A. baumannii</i>. |
<br/><br/> | <br/><br/> | ||
− | According to the study related to A. baumannii conducted by Lin et al. (Ref1_xerC), they concluded that XerC | + | According to the study related to <i>A. baumannii</i> conducted by Lin <i>et al.</i> (Ref1_xerC), they concluded that XerC |
and XerD are functional proteins and participate in horizontal dissemination of resistant genes among | and XerD are functional proteins and participate in horizontal dissemination of resistant genes among | ||
bacteria. The horizontal dissemination or transfer of resistance genes is a major cause of the increase in | bacteria. The horizontal dissemination or transfer of resistance genes is a major cause of the increase in | ||
− | Antibiotic resistance. Furthermore, the study conducted by Merino et al. (Ref2_xerC), finds that DNA | + | Antibiotic resistance. Furthermore, the study conducted by Merino <i>et al.</i> (Ref2_xerC), finds that DNA |
recombination through the Xer system in plasmids requires XerC and XerD (recombinases). DNA recombination | recombination through the Xer system in plasmids requires XerC and XerD (recombinases). DNA recombination | ||
helps in the natural editing of the bacterial genome and makes the natural process of evolution faster. | helps in the natural editing of the bacterial genome and makes the natural process of evolution faster. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: Since A. baumannii is an opportunistic pathogen that is evolving at a faster rate, and as | + | <b>Importance:</b> Since <i>A. baumannii</i> is an opportunistic pathogen that is evolving at a faster rate, and as |
− | mentioned above, xerC helps in DNA recombination which leads to natural editing of the genome, becomes an | + | mentioned above, <i>xerC </i>helps in DNA recombination which leads to natural editing of the genome, becomes an |
important target or pathway to be explored using wet-lab experiments. | important target or pathway to be explored using wet-lab experiments. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>asnC</b> </i>(Levofloxacin)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | asnC encodes for a regulatory protein called AsnC (UP_asnc). | + | <i>asnC </i>encodes for a regulatory protein called AsnC (UP_asnc). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Amino acid-binding, DNA-binding transcription activity, and Sequence-specific DNA | + | <b>GO Molecular function</b>: Amino acid-binding, DNA-binding transcription activity, and Sequence-specific DNA |
binding | binding | ||
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Positive and negative regulation of transcription, Response to amino acid | + | <b>GO Biological function</b>: Positive and negative regulation of transcription, Response to amino acid |
<br/><br/> | <br/><br/> | ||
Complete annotation: GO_asnC | Complete annotation: GO_asnC | ||
<br/><br/> | <br/><br/> | ||
− | The study conducted by Gebhardt et al. (Ref1_asnC), finds the list of around 300 genes which are important for | + | The study conducted by Gebhardt <i>et al.</i> (Ref1_asnC), finds the list of around 300 genes which are important for |
− | the survival and growth of A. baumannii, and find two AsnC/Lrp family regulators as putative transcriptional | + | the survival and growth of <i>A. baumannii</i>, and find two AsnC/Lrp family regulators as putative transcriptional |
regulators. | regulators. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: The involvement of asnC in amino acid binding and impacting the process of transcription makes it | + | <b>Importance:</b> The involvement of <i>asnC </i>in amino acid binding and impacting the process of transcription makes it |
an interesting pathway to be explored using wet-lab experiments. Like, aroP, it helps bacteria in performing | an interesting pathway to be explored using wet-lab experiments. Like, aroP, it helps bacteria in performing | ||
basic cellular functions which are essential for survival and growth. | basic cellular functions which are essential for survival and growth. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>puuP</b> </i>(Levofloxacin)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | puuP encodes for putrescine importer PuuP (UP_puuP) | + | <i>puuP </i>encodes for putrescine importer PuuP (UP_puuP) |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Putrescine transmembrane transporter activity | + | <b>GO Molecular function</b>: Putrescine transmembrane transporter activity |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Amino acid transport and cellular response to DNA damage stimulus | + | <b>GO Biological function</b>: Amino acid transport and cellular response to DNA damage stimulus |
<br/><br/> | <br/><br/> | ||
Complete annotation: GO_puuP | Complete annotation: GO_puuP | ||
<br/><br/> | <br/><br/> | ||
− | It is involved in the uptake of Putrescine, and according to a study conducted by Terui et al. (Ref1_puuP) it | + | It is involved in the uptake of Putrescine, and according to a study conducted by Terui <i>et al.</i> (Ref1_puuP) it |
helps in the import of putrescine to be utilized as an energy resource in absence of glucose. Further, it has | helps in the import of putrescine to be utilized as an energy resource in absence of glucose. Further, it has | ||
a biological process of helping in the cellular response to DNA damage, and given the fact that Levofloxacin | a biological process of helping in the cellular response to DNA damage, and given the fact that Levofloxacin | ||
Line 321: | Line 395: | ||
be explored. | be explored. | ||
<br/><br/> | <br/><br/> | ||
− | According to the study by Hassan et al. (Ref2_puuP), A. baumannii encodes for the transport protein AceI, | + | According to the study by Hassan <i>et al.</i> (Ref2_puuP), <i>A. baumannii</i> encodes for the transport protein AceI, |
which confers resistance to chlorhexidine, a widely used antiseptic. They also concluded that several gene | which confers resistance to chlorhexidine, a widely used antiseptic. They also concluded that several gene | ||
− | expression studies have revealed that the aceI gene responsible for encoding AceI protein is induced in A. | + | expression studies have revealed that the <i>aceI</i> gene responsible for encoding AceI protein is induced in A. |
baumannii by the short-chain diamines cadaverine and putrescine. It helps us in understanding the indirect | baumannii by the short-chain diamines cadaverine and putrescine. It helps us in understanding the indirect | ||
− | involvement of putrescine imported by puuP in antibiotic resistance. | + | involvement of putrescine imported by <i>puuP </i>in antibiotic resistance. |
<br/><br/> | <br/><br/> | ||
− | Importance: puuP helps in conferring resistance to chlorhexidine, it would be very important to check for the | + | <b>Importance:</b> <i>puuP </i>helps in conferring resistance to chlorhexidine, it would be very important to check for the |
− | same in the case of Levofloxacin especially for A. baumannii. | + | same in the case of Levofloxacin especially for <i>A. baumannii</i>. |
</p> | </p> | ||
<!--Links to be added (garbage links)--> | <!--Links to be added (garbage links)--> | ||
+ | <p class="wiki-p"> | ||
+ | GO_esiB: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A0A0H2VDN9<br/> | ||
+ | GO_aroP: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P15993<br/> | ||
+ | GO_tnsB: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P13989<br/> | ||
+ | GO_xerC: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0A8P6<br/> | ||
+ | GO_asnC: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0ACI6<br/> | ||
+ | GO_puuP: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P76037<br/> | ||
+ | <br/> | ||
+ | UP_esiB: https://www.uniprot.org/uniprot/A0A0H2VDN9<br/> | ||
+ | UP_aroP: https://www.uniprot.org/uniprot/P15993<br/> | ||
+ | UP_tnsB: https://www.uniprot.org/uniprot/P13989<br/> | ||
+ | UP_xerC: https://www.uniprot.org/uniprot/P0A8P6<br/> | ||
+ | UP_asnc: https://www.uniprot.org/uniprot/P0ACI6<br/> | ||
+ | UP_puuP: https://www.uniprot.org/uniprot/P76037<br/> | ||
+ | <br/> | ||
+ | Ref1_esiB: https://pubmed.ncbi.nlm.nih.gov/23882011/<br/> | ||
+ | Ref1_tnsB: https://www.sciencedirect.com/science/article/pii/S1517838216305330<br/> | ||
+ | Ref1_xerC: https://www.mdpi.com/2079-6382/9/7/405<br/> | ||
+ | Ref2_xerC: https://aac.asm.org/content/54/6/2724<br/> | ||
+ | Ref1_puuP: https://link.springer.com/article/10.1007/s00726-013-1517-x<br/> | ||
+ | Ref2_puuP: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731653/<br/> | ||
+ | |||
+ | </p> | ||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
</div> | </div> | ||
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</button> | </button> | ||
<div class="wiki-collapsed-content"> | <div class="wiki-collapsed-content"> | ||
− | < | + | |
− | < | + | |
+ | |||
+ | |||
+ | |||
+ | |||
+ | <table class="table table-hover table-bordered side-wrapped-item"> | ||
+ | <thead class="thead-dark"> | ||
+ | <tr> | ||
+ | <th scope="col">Genes</th> | ||
+ | <th scope="col">Antibiotic</th> | ||
+ | <th scope="col">Gene Ontology<br/> Annotations</th> | ||
+ | <th scope="col">Mechanism of Action</th> | ||
+ | <th scope="col">References</th> | ||
+ | </tr> | ||
+ | </thead> | ||
+ | <tbody> | ||
+ | <tr> | ||
+ | <td><i>aadB</i></td> | ||
+ | <td>Gentamicin | ||
+ | Tobramycin | ||
+ | Amikacin | ||
+ | </td> | ||
+ | <td>GO_aadB</td> | ||
+ | <td>Antibiotic inactivation</td> | ||
+ | <td>CARD_aadB, Ref1_aadB, Ref2_aadB, Ref3_aadB, Ref4_aadB</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>neo</i></td> | ||
+ | <td>Gentamicin | ||
+ | Tobramycin | ||
+ | Amikacin | ||
+ | </td> | ||
+ | <td>GO_neo</td> | ||
+ | <td>Kanamycin kinase activity</td> | ||
+ | <td>-</td> | ||
+ | |||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>msr(E)</i></td> | ||
+ | <td></td> | ||
+ | <td>GO_msrE</td> | ||
+ | <td>Plasmid DNA</td> | ||
+ | <td>Ref1_msrE, Ref2_msrE, Ref3_msrE, Ref4_msrE</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>emrE</i></td> | ||
+ | <td>Gentamicin</td> | ||
+ | <td>GO_emrE</td> | ||
+ | <td>Antibiotic efflux</td> | ||
+ | <td>CARD_emrE</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>cysL</i></td> | ||
+ | <td>Tobramycin</td> | ||
+ | <td>GO_cysL</td> | ||
+ | <td>DNA binding</td> | ||
+ | <td>-</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td><i>rmtB</i></td> | ||
+ | <td>Amikacin</td> | ||
+ | <td>GO_rmtB</td> | ||
+ | <td>Antibiotic target alteration</td> | ||
+ | <td>CARD_rmtB, Ref1_rmtB, Ref2_rmtB, Ref3_rmtB, Ref4_rmtB </td> | ||
+ | </tr> | ||
+ | |||
+ | </tbody> | ||
+ | </table> | ||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>aadB</b> </i>(Gentamicin, Tobramycin and Amikacin)</h4> | ||
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | aadB encodes for 2''-aminoglycoside nucleotidyltransferase (UP_aadB) | + | <i>aadB </i>encodes for 2''-aminoglycoside nucleotidyltransferase (UP_aadB) |
<br/><br/> | <br/><br/> | ||
It helps in mediating bacterial resistance to kanamycin, gentamicin, dibekacin, sisomicin, and tobramycin by | It helps in mediating bacterial resistance to kanamycin, gentamicin, dibekacin, sisomicin, and tobramycin by | ||
− | adenylate the 2''-hydroxyl group of these antibiotics in K. pneumoniae (UP_Kp_aadB) and kanamycin, gentamicin, | + | adenylate the 2''-hydroxyl group of these antibiotics in <i>K. pneumoniae </i>(UP_Kp_aadB) and kanamycin, gentamicin, |
− | and tobramycin in E. coli (UP_aadB). | + | and tobramycin in <i>E. coli</i> (UP_aadB). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Aminoglycoside 2''-nucleotidyltransferase activity, and Metal ion binding | + | <b>GO Molecular function</b>: Aminoglycoside 2''-nucleotidyltransferase activity, and Metal ion binding |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Response to antibiotic and Antibiotic resistance | + | <b>GO Biological function</b>: Response to antibiotic and Antibiotic resistance |
<br/><br/> | <br/><br/> | ||
Complete annotation: GO_aadB | Complete annotation: GO_aadB | ||
<br/><br/> | <br/><br/> | ||
− | aadB is a resistance-conferring gene which is confirmed by one of the most essential and relevant databases | + | <i>aadB </i>is a resistance-conferring gene which is confirmed by one of the most essential and relevant databases |
i.e. The Comprehensive Antibiotic Resistance Database (CARD). It works by the mechanism of antibiotic | i.e. The Comprehensive Antibiotic Resistance Database (CARD). It works by the mechanism of antibiotic | ||
inactivation and confers resistance to aminoglycoside antibiotics (CARD_aadB). | inactivation and confers resistance to aminoglycoside antibiotics (CARD_aadB). | ||
<br/><br/> | <br/><br/> | ||
− | The study conducted by Rizk et al. (Ref1_aadB) involves the collection of clinical samples of A. baumannii | + | The study conducted by Rizk <i>et al.</i> (Ref1_aadB) involves the collection of clinical samples of <i>A. baumannii</i> |
strains from intensive care units (ICUs) patients with suspected hospital-acquired infections followed by | strains from intensive care units (ICUs) patients with suspected hospital-acquired infections followed by | ||
checking them for resistance to aminoglycoside antibiotics. The study concluded that the most common prevalent | checking them for resistance to aminoglycoside antibiotics. The study concluded that the most common prevalent | ||
− | resistant genes among A. baumannii resistance to aminoglycosides was aadB with a contribution towards | + | resistant genes among <i>A. baumannii</i> resistance to aminoglycosides was <i>aadB </i>with a contribution towards |
antibiotic resistance as high as 42%. Since this study involves strains taken from hospitals with suspected | antibiotic resistance as high as 42%. Since this study involves strains taken from hospitals with suspected | ||
infections, it makes it essential for our novel protein-based drug to be checked for its efficacy against | infections, it makes it essential for our novel protein-based drug to be checked for its efficacy against | ||
aadB. | aadB. | ||
<br/><br/> | <br/><br/> | ||
− | As per the study by Anderson et al. (Ref2_aadB), in A. baumannii AB5075, a large plasmid (p1AB5075) carries | + | As per the study by Anderson <i>et al.</i> (Ref2_aadB), in <i>A. baumannii</i> AB5075, a large plasmid (p1AB5075) carries |
aadB, a 2″-nucleotidyltransferase that confers resistance to both tobramycin and gentamicin but not amikacin. | aadB, a 2″-nucleotidyltransferase that confers resistance to both tobramycin and gentamicin but not amikacin. | ||
− | It is very important in the case of our machine learning approach since our approach ranks aadB as the most | + | It is very important in the case of our machine learning approach since our approach ranks <i>aadB </i>as the most |
important feature (gene/allele) in the case of Gentamicin and Tobramycin but not in the case of Amikacin. | important feature (gene/allele) in the case of Gentamicin and Tobramycin but not in the case of Amikacin. | ||
<br/><br/> | <br/><br/> | ||
− | The study conducted by Chan et al. (Ref3_aadB), found a novel antibiotic resistance island in A. baumannii by | + | The study conducted by Chan <i>et al.</i> (Ref3_aadB), found a novel antibiotic resistance island in <i>A. baumannii</i> by |
analyzing genomes of several isolates collected from the US hospital system. They further concluded that after | analyzing genomes of several isolates collected from the US hospital system. They further concluded that after | ||
sequencing the genomes to completion, they found tobramycin-resistance gene aadB. | sequencing the genomes to completion, they found tobramycin-resistance gene aadB. | ||
<br/><br/> | <br/><br/> | ||
− | Si-Tuan et al., (Ref4_aadB) characterized the genome of the A. baumannii strain DMS06669 which was isolated | + | Si-Tuan <i>et al.</i>, (Ref4_aadB) characterized the genome of the <i>A. baumannii</i> strain DMS06669 which was isolated |
from the sputum of a male patient with hospital-acquired pneumonia, and identified genes related to antibiotic | from the sputum of a male patient with hospital-acquired pneumonia, and identified genes related to antibiotic | ||
− | resistance. They find aadB which is majorly resistant to gentamicin, as one of the genes responsible for | + | resistance. They find <i>aadB </i>which is majorly resistant to gentamicin, as one of the genes responsible for |
conferring resistance in the strain. | conferring resistance in the strain. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: These several studies make it very clear that aadB is an important gene especially considering | + | <b>Importance:</b> These several studies make it very clear that <i>aadB </i>is an important gene especially considering |
− | aminoglycoside antibiotics. Moreover, the presence of resistance by aadB to majorly gentamicin and tobramycin | + | aminoglycoside antibiotics. Moreover, the presence of resistance by <i>aadB </i>to majorly gentamicin and tobramycin |
− | but not amikacin further validates the effectiveness of our machine learning analysis as aadB was the top | + | but not amikacin further validates the effectiveness of our machine learning analysis as <i>aadB </i>was the top |
feature in the first two antibiotics but not in the latter. | feature in the first two antibiotics but not in the latter. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>neo </b></i>(Gentamicin, Tobramycin and Amikacin) </h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | neo encodes Aminoglycoside 3'-phosphotransferase (UP_neo) | + | <i>neo </i>encodes Aminoglycoside 3'-phosphotransferase (UP_neo) |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: ATP binding, Kanamycin kinase activity | + | <b>GO Molecular function</b>: ATP binding, Kanamycin kinase activity |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Response to antibiotic and Antibiotic resistance | + | <b>GO Biological function</b>: Response to antibiotic and Antibiotic resistance |
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_neo | + | <b>Complete GO annotation</b>: GO_neo |
<br/><br/> | <br/><br/> | ||
It helps in providing resistance to kanamycin, neomycin, paromomycin, ribostamycin, butirosin, and gentamicin | It helps in providing resistance to kanamycin, neomycin, paromomycin, ribostamycin, butirosin, and gentamicin | ||
− | B in the case of K. pneumoniae. This enzyme is encoded by the kanamycin and neomycin resistance transposon | + | B in the case of <i>K. pneumoniae</i>. This enzyme is encoded by the kanamycin and neomycin resistance transposon |
Tn5. Tn5 was originally isolated from K.pneumoniae, but has been transferred to a number of bacteria including | Tn5. Tn5 was originally isolated from K.pneumoniae, but has been transferred to a number of bacteria including | ||
− | E.coli. Since it has been transferred to E. coli, it is quite important to check for its relevance in the case | + | E.coli. Since it has been transferred to <i>E. coli</i>, it is quite important to check for its relevance in the case |
− | of A. baumannii. | + | of <i>A. baumannii</i>. |
<br/><br/> | <br/><br/> | ||
− | Importance: There has been a lack of literature studies conducted for neo in the context of A. baumannii, but | + | <b>Importance:</b> There has been a lack of literature studies conducted for <i>neo </i>in the context of <i>A. baumannii</i>, but |
it targets using protein pathway which is similar in mechanism to aminoglycoside antibiotics. Moreover, as | it targets using protein pathway which is similar in mechanism to aminoglycoside antibiotics. Moreover, as | ||
− | mentioned before, it would be interesting to check for its relevance in A. baumannii. | + | mentioned before, it would be interesting to check for its relevance in <i>A. baumannii</i>. |
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>msr(E)</b> </i>(Gentamicin, Tobramycin and Amikacin)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | msr(E) encodes for ABC-F type ribosomal protection protein (UP_msrE). | + | <i>msr(E) </i>encodes for ABC-F type ribosomal protection protein (UP_msrE). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: ATPase binding and ATP binding | + | <b>GO Molecular function</b>: ATPase binding and ATP binding |
<br/><br/> | <br/><br/> | ||
Complete annotation: GO_msrE | Complete annotation: GO_msrE | ||
<br/><br/> | <br/><br/> | ||
− | msr(E) is a resistant conferring gene as per the Comprehensive Antibiotic Resistance Database (CARD) and | + | <i>msr(E) </i>is a resistant conferring gene as per the Comprehensive Antibiotic Resistance Database (CARD) and |
provides resistance through antibiotic target alteration (CARD_msrE). Furthermore, as per CARD, Msr(E) is an | provides resistance through antibiotic target alteration (CARD_msrE). Furthermore, as per CARD, Msr(E) is an | ||
− | ABC-F subfamily protein expressed to K. pneumoniae that confers resistance to erythromycin and streptogramin B | + | ABC-F subfamily protein expressed to <i>K. pneumoniae </i>that confers resistance to erythromycin and streptogramin B |
antibiotics. It is associated with plasmid DNA. It is also 100% identical to ABC-F type ribosomal protection | antibiotics. It is associated with plasmid DNA. It is also 100% identical to ABC-F type ribosomal protection | ||
protein Msr(E) which is in multiple species. Since it is associated with plasmid DNA, it becomes an important | protein Msr(E) which is in multiple species. Since it is associated with plasmid DNA, it becomes an important | ||
factor in horizontal transfer and dissemination of antibiotic resistance. | factor in horizontal transfer and dissemination of antibiotic resistance. | ||
<br/><br/> | <br/><br/> | ||
− | Blackwell and Hall (Ref1_msrE) find in their study that macrolide resistance genes msrE and mphE were present | + | Blackwell and Hall (Ref1_msrE) find in their study that macrolide resistance genes msrE and <i>mphE</i> were present |
− | in an 18.2-kb plasmid of A. baumannii isolate from Singapore which confers resistance to erythromycin and | + | in an 18.2-kb plasmid of <i>A. baumannii</i> isolate from Singapore which confers resistance to erythromycin and |
tetracycline, both of which follow protein synthesis mechanism. | tetracycline, both of which follow protein synthesis mechanism. | ||
<br/><br/> | <br/><br/> | ||
− | A study conducted by Karah et al. (Ref2_msrE) concluded that msr(E) is one of the resistance genes present in | + | A study conducted by Karah <i>et al.</i> (Ref2_msrE) concluded that <i>msr(E) </i>is one of the resistance genes present in |
− | clinical isolates of A. baumannii in Pakistan. The study by Kumburu et al. (Ref3_msrE) utilized Whole Genome | + | clinical isolates of <i>A. baumannii</i> in Pakistan. The study by Kumburu <i>et al.</i> (Ref3_msrE) utilized Whole Genome |
− | Sequencing (WGS) to identify resistance-conferring genes in MDR A. baumannii in Tanzania. They found several | + | Sequencing (WGS) to identify resistance-conferring genes in MDR <i>A. baumannii</i> in Tanzania. They found several |
− | antibiotic resistance genes some of which were present in chromosomes while some on plasmids. msr(E) was | + | antibiotic resistance genes some of which were present in chromosomes while some on plasmids. <i>msr(E) </i>was |
detected as an antibiotic resistance gene that is present on plasmids and playing an important role in the | detected as an antibiotic resistance gene that is present on plasmids and playing an important role in the | ||
spreading of the resistance. | spreading of the resistance. | ||
<br/><br/> | <br/><br/> | ||
− | Similar to the case of aadB, the study conducted by Si-Tuan et al., (Ref4_aadB, Ref4_msrE) identified msr(E) | + | Similar to the case of aadB, the study conducted by Si-Tuan <i>et al.</i>, (Ref4_aadB, Ref4_msrE) identified msr(E) |
which is majorly resistant to streptogramin, which follows the similar mechanism as of aminoglycoside | which is majorly resistant to streptogramin, which follows the similar mechanism as of aminoglycoside | ||
antibiotics. | antibiotics. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: As shown by several studies, msr(E) is responsible for resistance to several antibiotics like | + | <b>Importance:</b> As shown by several studies, <i>msr(E) </i>is responsible for resistance to several antibiotics like |
macrolide, streptogramin, etc, which follow a similar mechanism to those of aminoglycosides, it becomes | macrolide, streptogramin, etc, which follow a similar mechanism to those of aminoglycosides, it becomes | ||
exciting and interesting to check for its relevance to Gentamicin, Tobramycin, and Amikacin. | exciting and interesting to check for its relevance to Gentamicin, Tobramycin, and Amikacin. | ||
Line 447: | Line 628: | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>emrE </b></i>(Gentamicin)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | emrE encodes for Multidrug transporter EmrE (UP_emrE). | + | <i>emrE </i>encodes for Multidrug transporter EmrE (UP_emrE). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Antiporter activity, Identical protein binding, etc. | + | <b>GO Molecular function</b>: Antiporter activity, Identical protein binding, etc. |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Cellular response to DNA damage stimulus, Response to drug, etc. | + | <b>GO Biological function</b>: Cellular response to DNA damage stimulus, Response to drug, etc. |
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_emrE | + | <b>Complete GO annotation</b>: GO_emrE |
<br/><br/> | <br/><br/> | ||
It is a multidrug efflux protein that confers resistance to a wide range of toxic compounds, including | It is a multidrug efflux protein that confers resistance to a wide range of toxic compounds, including | ||
Line 466: | Line 647: | ||
and works by antibiotic efflux mechanism to confer antibiotic resistance (CARD_emrE). | and works by antibiotic efflux mechanism to confer antibiotic resistance (CARD_emrE). | ||
<br/><br/> | <br/><br/> | ||
− | Importance: emrE is majorly found in P. aeruginosa and E. coli, which makes it quite interesting to check for | + | <b>Importance:</b> <i>emrE </i>is majorly found in <i>P. aeruginosa </i>and <i>E. coli</i>, which makes it quite interesting to check for |
− | existence on A. baumannii genomes. Moreover, it has been shown to be causing resistance to Tobramycin while | + | existence on <i>A. baumannii</i> genomes. Moreover, it has been shown to be causing resistance to Tobramycin while |
our machine learning detected it to be an important gene in the case of Gentamicin, so it would also be | our machine learning detected it to be an important gene in the case of Gentamicin, so it would also be | ||
exciting to validate and confirm by wet-lab experiments. | exciting to validate and confirm by wet-lab experiments. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>cysL</b> </i>(Tobramycin)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | cysL encodes for HTH-type transcriptional regulator CysL (UP_cysL). | + | <i>cysL </i>encodes for HTH-type transcriptional regulator CysL (UP_cysL). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: DNA-binding transcription factor activity | + | <b>GO Molecular function</b>: DNA-binding transcription factor activity |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: DNA-templated regulation of transcription | + | <b>GO Biological function</b>: DNA-templated regulation of transcription |
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_cysL | + | <b>Complete GO annotation</b>: GO_cysL |
<br/><br/> | <br/><br/> | ||
There is a lack of literature evidence in the case of cysL, but it has been identified as one of the topmost | There is a lack of literature evidence in the case of cysL, but it has been identified as one of the topmost | ||
features in the case of Tobramycin, and given the fact our machine learning has identified several genes | features in the case of Tobramycin, and given the fact our machine learning has identified several genes | ||
− | confirming to literature evidence, cysL is one of the novel genes uncovered by our algorithm responsible for | + | confirming to literature evidence, <i>cysL </i>is one of the novel genes uncovered by our algorithm responsible for |
antibiotic resistance. | antibiotic resistance. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: It would be interesting to check the relevance and importance of cysL in the context of A. | + | <b>Importance:</b> It would be interesting to check the relevance and importance of <i>cysL </i>in the context of A. |
baumannii and our novel protein-based drug as well, as it has been detected as the topmost feature by machine | baumannii and our novel protein-based drug as well, as it has been detected as the topmost feature by machine | ||
learning. | learning. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>rmtB</b> </i>(Amikacin)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | rmtB encodes for 16S rRNA (guanine(1405)-N(7))-methyltransferase (UP_rmtB). | + | <i>rmtB </i>encodes for 16S rRNA (guanine(1405)-N(7))-methyltransferase (UP_rmtB). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: rRNA methyltransferase activity | + | <b>GO Molecular function</b>: rRNA methyltransferase activity |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Response to antibiotic and Antibiotic resistance | + | <b>GO Biological function</b>: Response to antibiotic and Antibiotic resistance |
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_rmtB | + | <b>Complete GO annotation</b>: GO_rmtB |
<br/><br/> | <br/><br/> | ||
− | rmtB encoding protein specifically methylated the N7 position of guanine 1405 in 16S rRNA, and conferring | + | <i>rmtB </i>encoding protein specifically methylated the N7 position of guanine 1405 in 16S rRNA, and conferring |
resistance to various aminoglycosides (UP_rmtB). | resistance to various aminoglycosides (UP_rmtB). | ||
<br/><br/> | <br/><br/> | ||
Line 520: | Line 701: | ||
<br/><br/> | <br/><br/> | ||
− | Tada et al. (Ref1_rmtB) conducted a study on strains of A. baumannii and P. aeruginosa isolated from patients | + | Tada <i>et al.</i> (Ref1_rmtB) conducted a study on strains of <i>A. baumannii</i> and <i>P. aeruginosa </i>isolated from patients |
in intensive care units (ICUs) in two medical settings in Vietnam and out of which 71.3% strains were highly | in intensive care units (ICUs) in two medical settings in Vietnam and out of which 71.3% strains were highly | ||
resistant to amikacin and gentamicin. They further concluded that, 16S rRNA methylase RmtB was produced by 9 | resistant to amikacin and gentamicin. They further concluded that, 16S rRNA methylase RmtB was produced by 9 | ||
− | strains (of 101) of A. baumannii and 2 (of 15) strains of P. aeruginosa and 16S rRNA methylase producing | + | strains (of 101) of <i>A. baumannii</i> and 2 (of 15) strains of <i>P. aeruginosa </i>and 16S rRNA methylase producing |
organism are emerging. | organism are emerging. | ||
<br/><br/> | <br/><br/> | ||
− | The study by Lee et al. (Ref2_rmtB) analyzed amikacin resistant strains of gram-negative bacteria in Korea and | + | The study by Lee <i>et al.</i> (Ref2_rmtB) analyzed amikacin resistant strains of gram-negative bacteria in Korea and |
− | concluded that armA and rmtB were genes predominantly responsible for the resistance. | + | concluded that armA and <i>rmtB </i>were genes predominantly responsible for the resistance. |
<br/><br/> | <br/><br/> | ||
− | Wachino et al. (Ref3_rmtB) and Wang et al. (Ref4_rmtB) concluded that 16S rRNA methylases, which lead to the | + | Wachino <i>et al.</i> (Ref3_rmtB) and Wang <i>et al.</i> (Ref4_rmtB) concluded that 16S rRNA methylases, which lead to the |
high-level resistance of various aminoglycosides, can easily transfer to other bacteria since their genes are | high-level resistance of various aminoglycosides, can easily transfer to other bacteria since their genes are | ||
typically present on plasmids. The transfer of genes plays an important role in horizontal gene transfer and | typically present on plasmids. The transfer of genes plays an important role in horizontal gene transfer and | ||
the dissemination of antibiotic resistance. | the dissemination of antibiotic resistance. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: Several studies have indicated the spread of aminoglycoside resistance in A. baumannii which is a | + | <b>Importance:</b> Several studies have indicated the spread of aminoglycoside resistance in <i>A. baumannii</i> which is a |
major cause of worry for the researchers. Since our novel drug is protein-based therapeutic, it becomes | major cause of worry for the researchers. Since our novel drug is protein-based therapeutic, it becomes | ||
apparent to test our drug for its efficacy against such antibiotic-resistant genes. | apparent to test our drug for its efficacy against such antibiotic-resistant genes. | ||
</p> | </p> | ||
<!--Links to be added (garbage links)--> | <!--Links to be added (garbage links)--> | ||
+ | <p class="wiki-p"> | ||
+ | GO_aadB: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0AE04<br/> | ||
+ | GO_neo: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A0A086HV77<br/> | ||
+ | GO_msrE: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A5Y460<br/> | ||
+ | GO_emrE: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P23895<br/> | ||
+ | GO_cysL: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A0A0M3FB12<br/> | ||
+ | GO_rmtB: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=Q763K9<br/> | ||
+ | <br/> | ||
+ | UP_aadB: https://www.uniprot.org/uniprot/P0AE04<br/> | ||
+ | UP_Kp_aadB: https://www.uniprot.org/uniprot/P0AE05<br/> | ||
+ | UP_neo: https://www.uniprot.org/uniprot/P00552<br/> | ||
+ | UP_msrE: https://www.uniprot.org/uniprot/A5Y460<br/> | ||
+ | UP_emrE: https://www.uniprot.org/uniprot/P23895<br/> | ||
+ | UP_cysL: https://www.uniprot.org/uniprot/A0A0M3FB12<br/> | ||
+ | UP_rmtB: https://www.uniprot.org/uniprot/Q763K9<br/> | ||
+ | <br/> | ||
+ | CARD_aadB: https://card.mcmaster.ca/ontology/36369<br/> | ||
+ | CARD_emrE: https://card.mcmaster.ca/ontology/36403<br/> | ||
+ | CARD_rmtB: https://card.mcmaster.ca/ontology/37240<br/> | ||
+ | <br/> | ||
+ | Ref1_aadB: https://www.clin-lab-publications.com/article/3088<br/> | ||
+ | Ref2_aadB: https://msphere.asm.org/content/3/4/e00271-18<br/> | ||
+ | Ref3_aadB: https://academic.oup.com/jac/article-abstract/75/10/2760/5873331?redirectedFrom=fulltext<br/> | ||
+ | Ref4_aadB: https://ann-clinmicrob.biomedcentral.com/articles/10.1186/s12941-017-0250-9<br/> | ||
+ | Ref1_msrE: https://aac.asm.org/content/61/8/e00780-17<br/> | ||
+ | Ref2_msrE: https://ann-clinmicrob.biomedcentral.com/articles/10.1186/s12941-019-0344-7<br/> | ||
+ | Ref3_msrE: https://academic.oup.com/jac/article/74/6/1484/5370329<br/> | ||
+ | Ref4_msrE: https://ann-clinmicrob.biomedcentral.com/articles/10.1186/s12941-017-0250-9<br/> | ||
+ | Ref1_rmtB: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680199/<br/> | ||
+ | Ref2_rmtB: https://www.jkms.org/Synapse/Data/PDFData/0063JKMS/jkms-33-e262.pdf<br/> | ||
+ | Ref3_rmtB: https://pubmed.ncbi.nlm.nih.gov/17875999/<br/> | ||
+ | Ref4_rmtB: https://www.spandidos-publications.com/10.3892/etm.2016.3828#b13-etm-0-0-3828<br/> | ||
+ | |||
+ | </p> | ||
</div> | </div> | ||
Line 554: | Line 769: | ||
</button> | </button> | ||
<div class="wiki-collapsed-content"> | <div class="wiki-collapsed-content"> | ||
− | < | + | |
− | < | + | |
+ | |||
+ | |||
+ | |||
+ | |||
+ | <table class="table table-hover table-bordered side-wrapped-item"> | ||
+ | <thead class="thead-dark"> | ||
+ | <tr> | ||
+ | <th scope="col">Genes</th> | ||
+ | <th scope="col">Antibiotic</th> | ||
+ | <th scope="col">Gene Ontology<br/> Annotations</th> | ||
+ | <th scope="col">Mechanism of Action</th> | ||
+ | <th scope="col">References</th> | ||
+ | </tr> | ||
+ | </thead> | ||
+ | <tbody> | ||
+ | <tr> | ||
+ | <td>glmM</td> | ||
+ | <td>Ceftriaxone</td> | ||
+ | <td>GO_glmM</td> | ||
+ | <td>Phosphoglucosamine mutase protein</td> | ||
+ | <td>Ref1_glmM, Ref2_glmM, Ref3_glmM</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td>mshA</td> | ||
+ | <td>Ceftriaxone</td> | ||
+ | <td>GO_mshA</td> | ||
+ | <td>D-inositol 3-phosphate glycosyltransferase</td> | ||
+ | <td>CARD1_mshA, CARD2_mshA, CARD3_mshA</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td>relE</td> | ||
+ | <td>Imipenem</td> | ||
+ | <td>GO_relE</td> | ||
+ | <td>mRNA interferase toxin</td> | ||
+ | <td>Ref1_relE, Ref2_relE, CARD_relE</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td>tufA</td> | ||
+ | <td>Imipenem</td> | ||
+ | <td>GO_tufA</td> | ||
+ | <td>Elongation factor Tu 1</td> | ||
+ | <td>-</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td>yafQ</td> | ||
+ | <td>Ceftazidime</td> | ||
+ | <td>GO_yafQ</td> | ||
+ | <td>mRNA interferase toxin</td> | ||
+ | <td>-</td> | ||
+ | </tr> | ||
+ | <tr> | ||
+ | <td>eptA</td> | ||
+ | <td>Ceftazidime</td> | ||
+ | <td>GO_eptA</td> | ||
+ | <td>Phosphoethanolamine transferase</td> | ||
+ | <td>Ref1_eptA, Ref2_eptA, CARD_eptA</td> | ||
+ | </tr> | ||
+ | |||
+ | |||
+ | </tbody> | ||
+ | </table> | ||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | |||
+ | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>glmM</b> </i>(Ceftriaxone)</h4> | ||
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | glmM encodes for Phosphoglucosamine mutase protein (UP_glmM). | + | <i>glmM </i>encodes for Phosphoglucosamine mutase protein (UP_glmM). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Magnesium ion binding, Phosphoglucosamine mutase activity, and Phosphomannomutase | + | <b>GO Molecular function</b>: Magnesium ion binding, Phosphoglucosamine mutase activity, and Phosphomannomutase |
activity | activity | ||
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Carbohydrate metabolic process, Protein autophosphorylation, and | + | <b>GO Biological function</b>: Carbohydrate metabolic process, Protein autophosphorylation, and |
UDP-N-acetylglucosamine biosynthetic process | UDP-N-acetylglucosamine biosynthetic process | ||
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_glmM | + | <b>Complete GO annotation</b>: GO_glmM |
<br/><br/> | <br/><br/> | ||
− | Li et al. (Ref1_glmM) analyzed carbapenem-resistant clinical A. baumannii strains. They identified several | + | Li <i>et al.</i> (Ref1_glmM) analyzed carbapenem-resistant clinical <i>A. baumannii</i> strains. They identified several |
AbaR resistance islands for a better understanding of evolutionary processes contributing to the emergence of | AbaR resistance islands for a better understanding of evolutionary processes contributing to the emergence of | ||
− | carbapenem-resistant A. baumannii. As per their analysis, phosphoglucosamine mutase (GlmM) was detected in | + | carbapenem-resistant <i>A. baumannii</i>. As per their analysis, phosphoglucosamine mutase (GlmM) was detected in |
type 2, 7, and 10 AbaR islands. It is important to note that GlmM can catalyze the conversion of | type 2, 7, and 10 AbaR islands. It is important to note that GlmM can catalyze the conversion of | ||
glucosamine-6-phosphate to glucosamine-1-phosphate, which is an essential step in the formation of the cell | glucosamine-6-phosphate to glucosamine-1-phosphate, which is an essential step in the formation of the cell | ||
Line 578: | Line 867: | ||
synthesis of UDP-D-GlcpNAc. | synthesis of UDP-D-GlcpNAc. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: There are several studies stating that glmM encodes for the formation of cell wall precursors, and | + | <b>Importance:</b> There are several studies stating that <i>glmM </i>encodes for the formation of cell wall precursors, and |
it has been detected as one of the top features in the case of Ceftriaxone which also works with the mechanism | it has been detected as one of the top features in the case of Ceftriaxone which also works with the mechanism | ||
of bacterial cell wall synthesis. So, our machine learning algorithm has identified genes involved in the | of bacterial cell wall synthesis. So, our machine learning algorithm has identified genes involved in the | ||
Line 585: | Line 874: | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>mshA</b> </i>(Ceftriaxone)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | mshA encodes for D-inositol 3-phosphate glycosyltransferase (UP_mshA). | + | <i>mshA </i>encodes for D-inositol 3-phosphate glycosyltransferase (UP_mshA). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Acetylglucosaminyltransferase activity, transferring glycosyl groups | + | <b>GO Molecular function</b>: Acetylglucosaminyltransferase activity, transferring glycosyl groups |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Mycothiol biosynthetic process | + | <b>GO Biological function</b>: Mycothiol biosynthetic process |
<br/><br/> | <br/><br/> | ||
Complete annotation: GO_mshA | Complete annotation: GO_mshA | ||
Line 599: | Line 888: | ||
<br/><br/> | <br/><br/> | ||
The Comprehensive Antibiotic Resistance Database (CARD) provides several evidences for the involvement of mshA | The Comprehensive Antibiotic Resistance Database (CARD) provides several evidences for the involvement of mshA | ||
− | in antibiotics targeting cell wall mechanisms. Mutations in mshA result in the inactivation of antibiotics and | + | in antibiotics targeting cell wall mechanisms. Mutations in <i>mshA </i>result in the inactivation of antibiotics and |
it works by the mechanism of antibiotic target alteration (CARD1_mshA). | it works by the mechanism of antibiotic target alteration (CARD1_mshA). | ||
<br/><br/> | <br/><br/> | ||
− | As mentioned above, mshA is glycosyltransferase and is involved in the first step of mycothiol biosynthesis. | + | As mentioned above, <i>mshA </i>is glycosyltransferase and is involved in the first step of mycothiol biosynthesis. |
− | This is a step that is required for growth in M. tuberculosis and resistance has been in the gene to | + | This is a step that is required for growth in <i>M. tuberculosis</i> and resistance has been in the gene to |
isoniazid, which is antibiotic inhibiting mycobacterial cell wall (CARD2_mshA). Further, the mutations in mshA | isoniazid, which is antibiotic inhibiting mycobacterial cell wall (CARD2_mshA). Further, the mutations in mshA | ||
− | confer resistance to isoniazid in M. tuberculosis (CARD3_mshA). | + | confer resistance to isoniazid in <i>M. tuberculosis</i> (CARD3_mshA). |
<br/><br/> | <br/><br/> | ||
− | Importance: Our machine learning approach identifies allele of mshA as one of the most important features in | + | <b>Importance:</b> Our machine learning approach identifies allele of <i>mshA </i>as one of the most important features in |
predicting resistance phenotype of strain, which in accordance with literature evidence related to mutations | predicting resistance phenotype of strain, which in accordance with literature evidence related to mutations | ||
− | in mshA causing antibiotic resistance. Moreover, it has been detected as one of the most important genes in | + | in <i>mshA </i>causing antibiotic resistance. Moreover, it has been detected as one of the most important genes in |
the case of Ceftriaxone, which also works with mechanisms of bacterial cell wall synthesis. | the case of Ceftriaxone, which also works with mechanisms of bacterial cell wall synthesis. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>relE</b> </i>(Imipenem)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | relE encodes for mRNA interferase toxin RelE (UP_relE). | + | <i>relE </i>encodes for mRNA interferase toxin RelE (UP_relE). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: DNA-binding transcription repressor activity, ribosome binding, rRNA binding | + | <b>GO Molecular function</b>: DNA-binding transcription repressor activity, ribosome binding, rRNA binding |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Cellular response to amino acid starvation, mRNA catabolic process, negative | + | <b>GO Biological function</b>: Cellular response to amino acid starvation, mRNA catabolic process, negative |
regulation of translation | regulation of translation | ||
<br/><br/> | <br/><br/> | ||
Line 626: | Line 915: | ||
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_relE | + | <b>Complete GO annotation</b>: GO_relE |
<br/><br/> | <br/><br/> | ||
− | relE encodes for mRNA interferase, and mRNA interferases play a role in bacterial persistence to antibiotics; | + | <i>relE </i>encodes for mRNA interferase, and mRNA interferases play a role in bacterial persistence to antibiotics; |
overexpression of this protein induces persisters resistant to ciprofloxacin and ampicillin (UP_relE, | overexpression of this protein induces persisters resistant to ciprofloxacin and ampicillin (UP_relE, | ||
Ref1_relE). | Ref1_relE). | ||
<br/><br/> | <br/><br/> | ||
− | relE is a part of type II toxin-antitoxin system relBE wherein it is toxin and relB is anti-toxin. In presence | + | <i>relE </i>is a part of type II toxin-antitoxin system relBE wherein it is toxin and relB is anti-toxin. In presence |
− | of unfavorable conditions, toxin relE sharply increases persisters (cells that neither grow nor die in the | + | of unfavorable conditions, toxin <i>relE </i>sharply increases persisters (cells that neither grow nor die in the |
presence of bactericidal agents) and are largely responsible for high levels of biofilm tolerance to | presence of bactericidal agents) and are largely responsible for high levels of biofilm tolerance to | ||
antimicrobials (CARD_relE). So it blocks the process of mRNA to protein conversion inhibiting cell growth. The | antimicrobials (CARD_relE). So it blocks the process of mRNA to protein conversion inhibiting cell growth. The | ||
increase in biofilm tolerance makes it difficult for antibiotics to reach the bacteria for necessary action. | increase in biofilm tolerance makes it difficult for antibiotics to reach the bacteria for necessary action. | ||
<br/><br/> | <br/><br/> | ||
− | Pourhajibagher et al. (Ref2_relE) utilized the concept of this toxin-antitoxin system, relBE, for designing | + | Pourhajibagher <i>et al.</i> (Ref2_relE) utilized the concept of this toxin-antitoxin system, relBE, for designing |
Antimicrobial Photodynamic Therapy as an alternative to conventional antibiotic therapy using in-silico | Antimicrobial Photodynamic Therapy as an alternative to conventional antibiotic therapy using in-silico | ||
modeling and bioinformatics analysis. | modeling and bioinformatics analysis. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: There are several studies indicating the involvement of relE in being responsible for antibiotic | + | <b>Importance:</b> There are several studies indicating the involvement of <i>relE </i>in being responsible for antibiotic |
− | resistance, so it makes it interesting to look for its relevance in the case of A. baumannii using wet-lab | + | resistance, so it makes it interesting to look for its relevance in the case of <i>A. baumannii</i> using wet-lab |
experiments. | experiments. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>tufA</b> </i>(Imipenem)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | tufA encodes for the Elongation factor Tu 1 (UP_tufA). | + | <i>tufA </i>encodes for the Elongation factor Tu 1 (UP_tufA). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: GTPase activity, GTP binding | + | <b>GO Molecular function</b>: GTPase activity, GTP binding |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Translational elongation, Response to antibiotic and Antibiotic Resistance. | + | <b>GO Biological function</b>: Translational elongation, Response to antibiotic and Antibiotic Resistance. |
<br/><br/> | <br/><br/> | ||
Complet GO annotation: GO_tufA | Complet GO annotation: GO_tufA | ||
<br/><br/> | <br/><br/> | ||
− | The study conducted by Koenigs et al. (Ref1_tufA) showed for the first time that A. baumannii binds to | + | The study conducted by Koenigs <i>et al.</i> (Ref1_tufA) showed for the first time that <i>A. baumannii</i> binds to |
host-derived plasminogen with help of the translation elongation factor Tuf as a moonlighting | host-derived plasminogen with help of the translation elongation factor Tuf as a moonlighting | ||
− | plasminogen-binding protein that is exposed on the outer surface of A. baumannii. This binding phenomenon is | + | plasminogen-binding protein that is exposed on the outer surface of <i>A. baumannii</i>. This binding phenomenon is |
at least partly dependent on lysine residues and ionic interactions. Once bound to Tuf, plasminogen can be | at least partly dependent on lysine residues and ionic interactions. Once bound to Tuf, plasminogen can be | ||
converted to active plasmin and proteolytically degrade fibrinogen as well as the key complement component | converted to active plasmin and proteolytically degrade fibrinogen as well as the key complement component | ||
C3b. Therefore they concluded that Tuf acts as a multifunctional protein that may contribute to the virulence | C3b. Therefore they concluded that Tuf acts as a multifunctional protein that may contribute to the virulence | ||
− | of A. baumannii by aiding in dissemination and evasion of the complement system. | + | of <i>A. baumannii</i> by aiding in dissemination and evasion of the complement system. |
<br/><br/> | <br/><br/> | ||
− | Importance: The results of the above study clearly indicates the importance of Tuf protein is increasing and | + | <b>Importance:</b> The results of the above study clearly indicates the importance of Tuf protein is increasing and |
− | contributing to the virulence of A. baumannii. It would be interesting to explore more about the functioning | + | contributing to the virulence of <i>A. baumannii</i>. It would be interesting to explore more about the functioning |
and mechanism of this protein in the context of our novel protein-based drug-using wet-lab experiments. | and mechanism of this protein in the context of our novel protein-based drug-using wet-lab experiments. | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>yafQ</b> </i>(Ceftazidime)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | yafQ encodes for mRNA interferase toxin YafQ (UP_yafQ) | + | <i>yafQ </i>encodes for mRNA interferase toxin YafQ (UP_yafQ) |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: DNA binding, ribosome binding | + | <b>GO Molecular function</b>: DNA binding, ribosome binding |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: mRNA catabolic process, response to antibiotic | + | <b>GO Biological function</b>: mRNA catabolic process, response to antibiotic |
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_yafQ | + | <b>Complete GO annotation</b>: GO_yafQ |
<br/><br/> | <br/><br/> | ||
− | yafQ is working in a similar mechanism that of relE i.e. working as a toxin-antitoxin pair. YafQ protein pairs | + | <i>yafQ </i>is working in a similar mechanism that of <i>relE </i>i.e. working as a toxin-antitoxin pair. YafQ protein pairs |
with DinJ. which seems to play a role in biofilm formation. mRNA interferases play a role in bacterial | with DinJ. which seems to play a role in biofilm formation. mRNA interferases play a role in bacterial | ||
persistence to antibiotics (UP_yafQ). Since it helps in biofilm formation and biofilm can decrease the amount | persistence to antibiotics (UP_yafQ). Since it helps in biofilm formation and biofilm can decrease the amount | ||
Line 687: | Line 976: | ||
resistance. | resistance. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: It has not been explored much in the literature, and it would be really interesting to explore its | + | <b>Importance:</b> It has not been explored much in the literature, and it would be really interesting to explore its |
− | working in the context of A. baumannii along with relE as well. | + | working in the context of <i>A. baumannii</i> along with <i>relE </i>as well. |
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>eptA</b> </i>(Ceftazidime)</h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | eptA encodes Phosphoethanolamine transferase EptA (UP_eptA). | + | <i>eptA </i>encodes Phosphoethanolamine transferase EptA (UP_eptA). |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: phosphotransferase activity, sulfuric ester hydrolase activity | + | <b>GO Molecular function</b>: phosphotransferase activity, sulfuric ester hydrolase activity |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Lipid A biosynthesis, Antibiotic Resistance | + | <b>GO Biological function</b>: Lipid A biosynthesis, Antibiotic Resistance |
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_eptA | + | <b>Complete GO annotation</b>: GO_eptA |
<br/><br/> | <br/><br/> | ||
− | As per the Comprehensive Antibiotic Resistance Database (CARD), eptA mediates the modification Lipid A by the | + | As per the Comprehensive Antibiotic Resistance Database (CARD), <i>eptA </i>mediates the modification Lipid A by the |
addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosphoethanolamine which results in a less negative | addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosphoethanolamine which results in a less negative | ||
cell membrane and decreased binding of polymyxin B. It works by the mechanism of antibiotic target alteration | cell membrane and decreased binding of polymyxin B. It works by the mechanism of antibiotic target alteration | ||
(CARD_eptA). | (CARD_eptA). | ||
<br/><br/> | <br/><br/> | ||
− | The study conducted by Gerson et al. (Ref1_eptA) concluded that mutations in eptA were associated with | + | The study conducted by Gerson <i>et al.</i> (Ref1_eptA) concluded that mutations in <i>eptA </i>were associated with |
− | colistin resistance in A. baumannii. Trebsoc et al. (Ref2_eptA) suggested that direct targeting of the | + | colistin resistance in <i>A. baumannii</i>. Trebsoc <i>et al.</i> (Ref2_eptA) suggested that direct targeting of the |
− | homologous PetN transferases PmrC/EptA may have the potential to overcome colistin resistance in A. baumannii. | + | homologous PetN transferases PmrC/EptA may have the potential to overcome colistin resistance in <i>A. baumannii</i>. |
<br/><br/> | <br/><br/> | ||
− | Importance: eptA has been known to provide resistance to polymyxin B which works with the mechanism of | + | <b>Importance:</b> <i>eptA </i>has been known to provide resistance to polymyxin B which works with the mechanism of |
membrane disruption. It has been identified as one of the top genes for Ceftazidime which also works with the | membrane disruption. It has been identified as one of the top genes for Ceftazidime which also works with the | ||
mechanism of cell wall synthesis. Further, it has been studied to play a role in colistin resistance which | mechanism of cell wall synthesis. Further, it has been studied to play a role in colistin resistance which | ||
makes it very important and interesting to check for the efficacy of our novel protein-based drug against | makes it very important and interesting to check for the efficacy of our novel protein-based drug against | ||
eptA. | eptA. | ||
+ | </p> | ||
+ | <p> | ||
+ | GO_glmM: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P31120<br/> | ||
+ | GO_mshA: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P9WMY7<br/> | ||
+ | GO_relE: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0C077<br/> | ||
+ | GO_tufA: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0CE47<br/> | ||
+ | GO_yafQ: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=Q47149<br/> | ||
+ | GO_aptA: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P30845<br/> | ||
+ | <br/> | ||
+ | UP_glmM: https://www.uniprot.org/uniprot/P31120<br/> | ||
+ | UP_mshA: https://www.uniprot.org/uniprot/P9WMY7<br/> | ||
+ | UP_relE: https://www.uniprot.org/uniprot/P0C077<br/> | ||
+ | UP_tufA: https://www.uniprot.org/uniprot/P0CE47<br/> | ||
+ | UP_yafQ: https://www.uniprot.org/uniprot/Q47149<br/> | ||
+ | UP_eptA: https://www.uniprot.org/uniprot/P30845<br/> | ||
+ | <br/> | ||
+ | <br/> | ||
+ | CARD1_mshA: https://card.mcmaster.ca/ontology/43086<br/> | ||
+ | CARD2_mshA: https://card.mcmaster.ca/ontology/43087<br/> | ||
+ | CARD3_mshA: https://card.mcmaster.ca/ontology/43111<br/> | ||
+ | CARD_relE: https://card.mcmaster.ca/ontology/40753<br/> | ||
+ | CARD_eptA: https://card.mcmaster.ca/ontology/40186<br/> | ||
+ | <br/> | ||
+ | Ref1_glmM: https://aac.asm.org/content/59/2/1168<br/> | ||
+ | Ref2_glmM: https://pubmed.ncbi.nlm.nih.gov/10913078/<br/> | ||
+ | Ref3_glmM: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628348/<br/> | ||
+ | Ref1_relE: https://pubmed.ncbi.nlm.nih.gov/21788497/<br/> | ||
+ | Ref2_relE: https://www.derpharmachemica.com/pharma-chemica/in-silico-modeling-of-releb-type-ii-toxinantitoxin-system-in-acinetobacter-baumannii-as-a-therapeutic-target-via-antimicrobial-pho-14977.html<br/> | ||
+ | Ref1_eptA: https://aac.asm.org/content/63/3/e01586-18<br/> | ||
+ | Ref2_eptA: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635527/<br/> | ||
+ | |||
</p> | </p> | ||
</div> | </div> | ||
Line 739: | Line 1,059: | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>folP</b> </i></h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | folP encodes for Dihydropteroate synthase (UP_folP) | + | <i>folP </i>encodes for Dihydropteroate synthase (UP_folP) |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Dihydropteroate synthase activity, and metal ion binding | + | <b>GO Molecular function</b>: Dihydropteroate synthase activity, and metal ion binding |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Folate biosynthesis and Response to drug | + | <b>GO Biological function</b>: Folate biosynthesis and Response to drug |
<br/><br/> | <br/><br/> | ||
GO Cellular component: Cytoplasm and Cytosol | GO Cellular component: Cytoplasm and Cytosol | ||
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_folP | + | <b>Complete GO annotation</b>: GO_folP |
<br/><br/> | <br/><br/> | ||
Line 757: | Line 1,077: | ||
<br/><br/> | <br/><br/> | ||
As per the Comprehensive Antibiotic Resistance Database (CARD), point mutations in dihydropteroate synthase, | As per the Comprehensive Antibiotic Resistance Database (CARD), point mutations in dihydropteroate synthase, | ||
− | folP prevent sulfonamide antibiotics from inhibiting its role in folate synthesis, thus conferring sulfonamide | + | <i>folP </i>prevent sulfonamide antibiotics from inhibiting its role in folate synthesis, thus conferring sulfonamide |
resistance (CARD_folP). It works with the mechanism of antibiotic target alteration. Our machine learning | resistance (CARD_folP). It works with the mechanism of antibiotic target alteration. Our machine learning | ||
− | approach identified folP and its alleles as the topmost important features which further validate the efficacy | + | approach identified <i>folP </i>and its alleles as the topmost important features which further validate the efficacy |
of our algorithm. | of our algorithm. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: The detection of folP in the case of antibiotics working with folate disruption by machine | + | <b>Importance:</b> The detection of <i>folP </i>in the case of antibiotics working with folate disruption by machine |
learning algorithm is a very important indication for the efficacy of the approach. It would be very | learning algorithm is a very important indication for the efficacy of the approach. It would be very | ||
− | interesting to check for the impact of folP in establishing resistance to our novel protein-based drug. | + | interesting to check for the impact of <i>folP </i>in establishing resistance to our novel protein-based drug. |
</p> | </p> | ||
</div> | </div> | ||
Line 789: | Line 1,109: | ||
</p> | </p> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>bla</b> </i></h4> |
<p class="wiki-p"> | <p class="wiki-p"> | ||
− | bla encodes for Beta-lactamase TEM | + | <i>bla </i>encodes for Beta-lactamase TEM |
<br/><br/> | <br/><br/> | ||
− | GO Molecular function: Beta-lactamase activity | + | <b>GO Molecular function</b>: Beta-lactamase activity |
<br/><br/> | <br/><br/> | ||
− | GO Biological function: Beta-lactam antibiotic catabolic process, response to antibiotic and Antibiotic | + | <b>GO Biological function</b>: Beta-lactam antibiotic catabolic process, response to antibiotic and Antibiotic |
resistance | resistance | ||
<br/><br/> | <br/><br/> | ||
− | Complete GO annotation: GO_bla | + | <b>Complete GO annotation</b>: GO_bla |
<br/><br/> | <br/><br/> | ||
TEM-type is the most prevalent beta-lactamases in Enterobacteriaceae; they hydrolyze the beta-lactam bond in | TEM-type is the most prevalent beta-lactamases in Enterobacteriaceae; they hydrolyze the beta-lactam bond in | ||
susceptible beta-lactam antibiotics, thus conferring resistance to these antibiotics (UP_bla). | susceptible beta-lactam antibiotics, thus conferring resistance to these antibiotics (UP_bla). | ||
<br/><br/> | <br/><br/> | ||
− | The study conducted by Subramaniyan and Sundaram (Ref1_bla) concluded the presence of bla genes in | + | The study conducted by Subramaniyan and Sundaram (Ref1_bla) concluded the presence of <i>bla </i>genes in |
− | carbapenem-resistant P. aeruginosa and A. baumannii isolated from clinical settings, Intensive Care Unit | + | carbapenem-resistant <i>P. aeruginosa </i>and <i>A. baumannii</i> isolated from clinical settings, Intensive Care Unit |
− | (ICU). Further, the study by Kumar et al. (Ref2_bla) analyzed the carbapenem-resistant A. baumannii isolates | + | (ICU). Further, the study by Kumar <i>et al.</i> (Ref2_bla) analyzed the carbapenem-resistant <i>A. baumannii</i> isolates |
− | from two tertiary care hospitals of North India and concluded that bla encoding clones. It is an important | + | from two tertiary care hospitals of North India and concluded that <i>bla </i>encoding clones. It is an important |
discovery especially in the context of India hospital settings. | discovery especially in the context of India hospital settings. | ||
<br/><br/> | <br/><br/> | ||
− | Importance: Our machine learning algorithm identifies bla as the most important feature, which is also in the | + | <b>Importance:</b> Our machine learning algorithm identifies <i>bla </i>as the most important feature, which is also in the |
mechanism of Ampicillin and Sulbactam. It shows the efficacy of our approach. Moreover, the above studies | mechanism of Ampicillin and Sulbactam. It shows the efficacy of our approach. Moreover, the above studies | ||
− | clearly indicate the importance of bla gene in A. baumannii and it would be surely interesting to check for | + | clearly indicate the importance of <i>bla </i>gene in <i>A. baumannii</i> and it would be surely interesting to check for |
its relevance in the case of our novel protein-based drug. | its relevance in the case of our novel protein-based drug. | ||
+ | </p> | ||
+ | <p> | ||
+ | GO_folP: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0AC13<br/> | ||
+ | GO_bla: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P62593<br/> | ||
+ | <br/> | ||
+ | UP_folP: https://www.uniprot.org/uniprot/P0AC13<br/> | ||
+ | UP_bla: https://www.uniprot.org/uniprot/P62593<br/> | ||
+ | <br/> | ||
+ | CARD_folP: https://card.mcmaster.ca/ontology/36365<br/> | ||
+ | <br/> | ||
+ | Ref1_bla: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896190/<br/> | ||
+ | Ref2_bla: https://pubmed.ncbi.nlm.nih.gov/31362071/<br/> | ||
+ | |||
</p> | </p> | ||
</div> | </div> | ||
+ | |||
+ | <br/><br/><br/><br/> | ||
+ | |||
<h2 class="wiki-h wiki-h2 wiki-section-start" id="wiki_section_2"> | <h2 class="wiki-h wiki-h2 wiki-section-start" id="wiki_section_2"> | ||
+ | |||
Correlation and mutational analysis of gene-gene pair | Correlation and mutational analysis of gene-gene pair | ||
− | </h2> | + | </h2><br/> |
<!--dropdown6--> | <!--dropdown6--> | ||
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</button> | </button> | ||
<div class="wiki-collapsed-content"> | <div class="wiki-collapsed-content"> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>xerC vs. ssuC</b></i> (Ciprofloxacin)</h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
− | <img alt="" class="wiki-graphic-image" src="../ | + | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/3/32/T--IIT_Roorkee--images--images--ML_Results_ciprofloxacin_corr.png"/> |
</div> | </div> | ||
<ol class="wiki-ol"> | <ol class="wiki-ol"> | ||
Line 836: | Line 1,173: | ||
<li>Resistance increases with mutations in ssuC</li> | <li>Resistance increases with mutations in ssuC</li> | ||
<li>The increase in resistance with mutations in both genes confirm a positive correlation between them</li> | <li>The increase in resistance with mutations in both genes confirm a positive correlation between them</li> | ||
− | <li>Mutations in xerC are accompanied by an increase in resistance for all of the following, ssuC_1, ssuC_2, | + | <li>Mutations in <i>xerC </i>are accompanied by an increase in resistance for all of the following, ssuC_1, ssuC_2, |
ssuC_3, ssuC_4 and ssuC_5</li> | ssuC_3, ssuC_4 and ssuC_5</li> | ||
</ol> | </ol> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>puuP vs. astC</b></i> (Levofloxacin)</h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/6/6c/T--IIT_Roorkee--images--images--ML_Results_levofloxacin_analysis.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/6/6c/T--IIT_Roorkee--images--images--ML_Results_levofloxacin_analysis.png"/> | ||
Line 847: | Line 1,184: | ||
<li>astC is a gene important for resistance but strains became more susceptible in presence of puuP</li> | <li>astC is a gene important for resistance but strains became more susceptible in presence of puuP</li> | ||
<li>Mutations in astC causes a decrease in resistance </li> | <li>Mutations in astC causes a decrease in resistance </li> | ||
− | <li>Mutations in astC increase resistance in presence of puuP but decrease resistance with mutations in puuP | + | <li>Mutations in astC increase resistance in presence of <i>puuP </i>but decrease resistance with mutations in puuP |
which confirms a negative correlation</li> | which confirms a negative correlation</li> | ||
</ol> | </ol> | ||
Line 861: | Line 1,198: | ||
</button> | </button> | ||
<div class="wiki-collapsed-content"> | <div class="wiki-collapsed-content"> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>emrE vs.<i> folP</i> </b></i>(Gentamicin)</h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/e/ef/T--IIT_Roorkee--images--images--ML_Results_gentamicin_analysis.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/e/ef/T--IIT_Roorkee--images--images--ML_Results_gentamicin_analysis.png"/> | ||
Line 867: | Line 1,204: | ||
<ol class="wiki-ol"> | <ol class="wiki-ol"> | ||
<li>Resistance increases with mutations in emrE</li> | <li>Resistance increases with mutations in emrE</li> | ||
− | <li>Resistance increases with mutations in folP</li> | + | <li>Resistance increases with mutations in<i> folP</i></li> |
<li>Mutations in both the genes work in tandem and increase the resistance of strains confirming a positive | <li>Mutations in both the genes work in tandem and increase the resistance of strains confirming a positive | ||
correlation between them</li> | correlation between them</li> | ||
Line 873: | Line 1,210: | ||
</ol> | </ol> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>cysL vs. <i>hcaR </i></b></i>(Tobramycin) </h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/5/5b/T--IIT_Roorkee--images--images--ML_Results_tobramycin_analysis.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/5/5b/T--IIT_Roorkee--images--images--ML_Results_tobramycin_analysis.png"/> | ||
Line 880: | Line 1,217: | ||
<li>Resistance increases with mutations in cysL</li> | <li>Resistance increases with mutations in cysL</li> | ||
<li>Resistance decreases with mutations in hcaR</li> | <li>Resistance decreases with mutations in hcaR</li> | ||
− | <li>Mutations in hcaR increases the resistance but not when cysL is present confirming a negative correlation | + | <li>Mutations in <i>hcaR </i>increases the resistance but not when <i>cysL </i>is present confirming a negative correlation |
</li> | </li> | ||
</ol> | </ol> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>esiB vs. <i>cspV</i></b></i> (Amikacin) </h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/a/a4/T--IIT_Roorkee--images--images--ML_Results_amikacin_analysis.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/a/a4/T--IIT_Roorkee--images--images--ML_Results_amikacin_analysis.png"/> | ||
</div> | </div> | ||
<ol class="wiki-ol"> | <ol class="wiki-ol"> | ||
− | <li>Resistance decreases with mutations in esiB</li> | + | <li>Resistance decreases with mutations in <i>esiB</i></li> |
− | <li>Resistance decreases with mutations in cspV</li> | + | <li>Resistance decreases with mutations in <i>cspV</i></li> |
− | <li>Resistance in strains with cspV decreases or reaches zero with mutations in esiB confirming a positive | + | <li>Resistance in strains with <i><i>cspV</i> </i>decreases or reaches zero with mutations in <i>esiB </i>confirming a positive |
correlation</li> | correlation</li> | ||
</ol> | </ol> | ||
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</button> | </button> | ||
<div class="wiki-collapsed-content"> | <div class="wiki-collapsed-content"> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b><i>ssuA</i> vs. <i>ssuC </i></b></i>(Ceftriaxone) </h4> |
+ | |||
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/3/3c/T--IIT_Roorkee--images--images--ML_Results_ceftriaxone_analysis.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/3/3c/T--IIT_Roorkee--images--images--ML_Results_ceftriaxone_analysis.png"/> | ||
</div> | </div> | ||
<ol class="wiki-ol"> | <ol class="wiki-ol"> | ||
− | <li>There is lack of strains having ssuA and ssuC genes without mutations</li> | + | <li>There is lack of strains having <i>ssuA</i> and <i>ssuC </i>genes without mutations</li> |
− | <li>Resistance increases with mutations in ssuA</li> | + | <li>Resistance increases with mutations in <i>ssuA</i></li> |
− | <li>Resistance increases with mutations in ssuC which confirms a positive correlation between genes</li> | + | <li>Resistance increases with mutations in <i>ssuC </i>which confirms a positive correlation between genes</li> |
</ol> | </ol> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>tufA vs. <i>tufB </i></b></i>(Imipenem)</h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/d/d1/T--IIT_Roorkee--images--images--ML_Results_imipenem_analysis.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/d/d1/T--IIT_Roorkee--images--images--ML_Results_imipenem_analysis.png"/> | ||
</div> | </div> | ||
<ol class="wiki-ol"> | <ol class="wiki-ol"> | ||
− | <li>Resistance decreases with mutations in tufA </li> | + | <li>Resistance decreases with mutations in <i>tufA </i></li> |
− | <li>Resistance increases with mutations in tufB confirming a negative correlation between genes</li> | + | <li>Resistance increases with mutations in <i>tufB </i>confirming a negative correlation between genes</li> |
</ol> | </ol> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>aphA vs. <i>fatA </i></b></i>(Ceftazidime)</h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
− | <img alt="" class="wiki-graphic-image" src="../ | + | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/f/f7/T--IIT_Roorkee--images--images--ML_Results_ceftazidime_analysis.png"/> |
</div> | </div> | ||
<ol class="wiki-ol"> | <ol class="wiki-ol"> | ||
<li>Resistance increases with mutations in aphA</li> | <li>Resistance increases with mutations in aphA</li> | ||
− | <li>Resistance increases with mutations in fatA which confirms a positive correlation between genes</li> | + | <li>Resistance increases with mutations in <i>fatA </i>which confirms a positive correlation between genes</li> |
− | <li>There is less number of strains having fatA gene and much more number of strains with mutations in fatA | + | <li>There is less number of strains having <i>fatA </i>gene and much more number of strains with mutations in fatA |
</li> | </li> | ||
</ol> | </ol> | ||
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</button> | </button> | ||
<div class="wiki-collapsed-content"> | <div class="wiki-collapsed-content"> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b>folP vs. emrE</b></i></h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/7/71/T--IIT_Roorkee--images--images--ML_Results_t%2Bs_analysis.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/7/71/T--IIT_Roorkee--images--images--ML_Results_t%2Bs_analysis.png"/> | ||
</div> | </div> | ||
<ol class="wiki-ol"> | <ol class="wiki-ol"> | ||
− | <li>Resistance increases with mutations in folP</li> | + | <li>Resistance increases with mutations in<i> folP</i></li> |
− | <li>Resistance increases with mutations in emrE confirming a positive correlation between genes</li> | + | <li>Resistance increases with mutations in <i>emrE </i>confirming a positive correlation between genes</li> |
− | <li>There is less number of strains with folP and more number of strains with mutations in folP</li> | + | <li>There is less number of strains with <i>folP </i>and more number of strains with mutations in<i> folP</i></li> |
− | + | ||
</ol> | </ol> | ||
</div> | </div> | ||
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</button> | </button> | ||
<div class="wiki-collapsed-content"> | <div class="wiki-collapsed-content"> | ||
− | < | + | <br/><br/><h4 class="wiki-h wiki-h4"><i><b><i>mobA</i> vs. yddG</b></i></h4> |
<div class="wiki-graphic"> | <div class="wiki-graphic"> | ||
<img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/3/33/T--IIT_Roorkee--images--images--ML_Results_a%2Bs_analysis.png"/> | <img alt="" class="wiki-graphic-image" src="https://static.igem.org/mediawiki/2020/3/33/T--IIT_Roorkee--images--images--ML_Results_a%2Bs_analysis.png"/> | ||
</div> | </div> | ||
<ol class="wiki-ol"> | <ol class="wiki-ol"> | ||
− | <li>Resistance decreases with mutations in mobA</li> | + | <li>Resistance decreases with mutations in <i>mobA</i></li> |
− | <li>Resistance increases with mutations in yddG confirming a negative correlation between genes</li> | + | <li>Resistance increases with mutations in <i>yddG </i>confirming a negative correlation between genes</li> |
− | <li>Increased resistance due to mutations in yddG vanished with mutations in mobA</li> | + | <li>Increased resistance due to mutations in <i>yddG </i>vanished with mutations in <i>mobA</i></li> |
</ol> | </ol> | ||
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We have utilized a machine learning algorithm over the strain-gene/allele dataset of A. baumannii available from the PATRIC database that can predict the resistance phenotype of strains. In nutshell, we have used the presence or absence of particular genes or alleles as features in predicting the phenotype of strain. We have utilized the data of 1360 A. baumannii strains along with 10 different antibiotics.
The results of machine learning can be summarized in the following two points
- Detection of genes conferring antibiotic resistance
- Analysis of the effect of mutations on antibiotic resistance
Detection of Genes conferring Antibiotic resistance
The machine-learning algorithm has helped in the identification of genes that are either specific to the mechanism of the particular antibiotic or involved in the novel pathway or target. There are few genes that are involved in basic cellular processes that strongly relate to the survival and growth of A. baumannii. The genes corresponding to the particular antibiotic are listed below.
Genes | Antibiotic | Gene Ontology Annotations |
Mechanism of Action | References |
---|---|---|---|---|
esiB | iprofloxacin Levofloxacin | GO_esiB | Secretory immunoglobulin A-binding protein |
Ref1_esiB |
aroP | iprofloxacin Levofloxacin | GO_aroP | Aromatic amino acid transport protein |
- |
tnsB | Ciprofloxacin | GO_tnsB | Transposon Tn7 transposition protein | Ref1_tnsB |
xerC | Ciprofloxacin | GO_xerC | Tyrosine recombinase | Ref1_xerC, Ref2_xerC |
asnC | Levofloxacin | GO_asnC | Regulatory protein, AsnC | - |
puuP | Levofloxacin | GO_puup | Putrescine importer | Ref1_puuP, Ref2_puuP |
esiB (Ciprofloxacin and Levofloxacin)
esiB encodes for Secretory immunoglobulin A-binding protein (UP_esiB).
GO Molecular function: IgA binding and Metal ion binding
GO Biological function: Negative regulation of immune response and neutrophil activation, and pathogenesis
Complete GO annotation: GO_esiB
According to the study of Pastorello et al. (Ref1_esiB), they concluded that esiB helps in secretion of the
protein which binds with immunoglobulins in the blood or antibodies helping bacteria escape from neutrophil
(cell eating bacteria). The neutrophil is the most common White Blood Cells (WBC) in the human body, so these
proteins help the bacterial pathogen in escaping the immune system pathway in the patients of Urinary Tract
Infections. The study also concluded that esiB is preferentially associated with extraintestinal strains,
while the gene is rarely found in either intestinal or nonpathogenic strains.
Importance: The presence and importance of this gene in the case of patients with Urinary Tract Infection (one
of the major Hospital Acquired Infections) make it an important target/gene to explore using wet-lab
experiments in the case of A. baumannii.
aroP (Ciprofloxacin and Levofloxacin)
aroP encodes for Aromatic amino acid transport protein. It is a permease that is involved in the transport
across the cytoplasmic membrane of the aromatic amino acids (phenylalanine, tyrosine, and tryptophan),
(UP_aroP).
GO Molecular function: Transmembrane transporter activity of aromatic amino acids
GO Biological function: Amino acids transport
GO Cellular Component: Integral component of Plasma membrane
Complete GO annotation: GO_aroP
Since aroP helps in encoding protein responsible for transportation aromatic amino acids, therefore it is
related to very basic cellular functions. Amino acids are important for the process of transcription and
translation, their transportation plays an important role in these functions.
Importance: There is a lack of studies conducted for exploring the functioning of aroP in the context of A.
baumannii (UP2_aroP), which makes it a novel and important target pathway to be explored for using wet-lab
experiments, especially because it is involved in the basic cellular process i.e. amino acid transport.
tnsBtnsB (Ciprofloxacin)
tnsB encodes for Transposon Tn7 transposition protein, which are very special proteins helping in cutting,
pasting, and making copies of DNA in the chromosome (UP_tnsB).
GO Molecular function: DNA Binding, and Transposase activity
GO Biological function: DNA Integration and DNA-mediated transposition
GO Cellular Component: Cytoplasmic membrane
Complete GO annotation: GO_tnsB
Ciprofloxacin acts by inhibition of DNA replication by inhibiting bacterial DNA topoisomerase and DNA-gyrase.
Transposons help in DNA strand breakage which is also carried out by topoisomerase. These facts make it very
clear that tnsB is an important gene and target in the context of DNA replication and is involved in a similar
mechanism as that of Ciprofloxacin.
Tn7 class transposon proteins are associated with carbapenem-resistance in A. baumannii (Ref1_tnsB). The study
by Rose (Ref2_tnsB), discovered a novel Tn7-related transposon, TnAbaR1 which contributes to the accumulation
and dissemination of antibiotic resistance genes. According to their study, Tn7 is a well-studied, highly
promiscuous cut-and-paste transposon, found in a variety of bacteria and mainly important for resistance to
antibiotics such as trimethoprim and streptomycin.
Importance: The involvement of tnsB in being a cause of resistance to several antibiotics makes it an
important target and pathway to be explored especially in the context of our novel protein-based therapeutic
and our pathogen of interest, A. baumannii.
xerC (Ciprofloxacin)
xerC encodes for tyrosine recombinase, which acts by catalyzing the cutting and rejoining of the recombining
DNA molecules.
GO Molecular function: DNA binding, Site-specific recombinase activity
GO Biological function: Cell cycle, Cell division, and Chromosome segregation
GO Cellular Component: Cytoplasm
Complete GO annotation: GO_xerC
It binds cooperatively to specific DNA consensus sequences that are separated from XerD binding sites by a
short central region, forming the heterotetrameric XerC-XerD complex is essential to convert dimers of the
bacterial chromosome into monomers to permit their segregation at cell division. It also contributes to the
segregational stability of plasmid. (UP_xerC)
During the recombination phase, this complex catalyzes two consecutive pairs of strand exchanges, implying
that specific pairs of active sites are sequentially switched on and off in the recombinase tetramer to ensure
that appropriate DNA strands will be exchanged at both reaction steps. These findings have been made for E.
coli and it would be interesting to check for the same in the case of A. baumannii.
According to the study related to A. baumannii conducted by Lin et al. (Ref1_xerC), they concluded that XerC
and XerD are functional proteins and participate in horizontal dissemination of resistant genes among
bacteria. The horizontal dissemination or transfer of resistance genes is a major cause of the increase in
Antibiotic resistance. Furthermore, the study conducted by Merino et al. (Ref2_xerC), finds that DNA
recombination through the Xer system in plasmids requires XerC and XerD (recombinases). DNA recombination
helps in the natural editing of the bacterial genome and makes the natural process of evolution faster.
Importance: Since A. baumannii is an opportunistic pathogen that is evolving at a faster rate, and as
mentioned above, xerC helps in DNA recombination which leads to natural editing of the genome, becomes an
important target or pathway to be explored using wet-lab experiments.
asnC (Levofloxacin)
asnC encodes for a regulatory protein called AsnC (UP_asnc).
GO Molecular function: Amino acid-binding, DNA-binding transcription activity, and Sequence-specific DNA
binding
GO Biological function: Positive and negative regulation of transcription, Response to amino acid
Complete annotation: GO_asnC
The study conducted by Gebhardt et al. (Ref1_asnC), finds the list of around 300 genes which are important for
the survival and growth of A. baumannii, and find two AsnC/Lrp family regulators as putative transcriptional
regulators.
Importance: The involvement of asnC in amino acid binding and impacting the process of transcription makes it
an interesting pathway to be explored using wet-lab experiments. Like, aroP, it helps bacteria in performing
basic cellular functions which are essential for survival and growth.
puuP (Levofloxacin)
puuP encodes for putrescine importer PuuP (UP_puuP)
GO Molecular function: Putrescine transmembrane transporter activity
GO Biological function: Amino acid transport and cellular response to DNA damage stimulus
Complete annotation: GO_puuP
It is involved in the uptake of Putrescine, and according to a study conducted by Terui et al. (Ref1_puuP) it
helps in the import of putrescine to be utilized as an energy resource in absence of glucose. Further, it has
a biological process of helping in the cellular response to DNA damage, and given the fact that Levofloxacin
is involved in the mechanism of DNA replication which makes it a very interesting and prospective pathway to
be explored.
According to the study by Hassan et al. (Ref2_puuP), A. baumannii encodes for the transport protein AceI,
which confers resistance to chlorhexidine, a widely used antiseptic. They also concluded that several gene
expression studies have revealed that the aceI gene responsible for encoding AceI protein is induced in A.
baumannii by the short-chain diamines cadaverine and putrescine. It helps us in understanding the indirect
involvement of putrescine imported by puuP in antibiotic resistance.
Importance: puuP helps in conferring resistance to chlorhexidine, it would be very important to check for the
same in the case of Levofloxacin especially for A. baumannii.
GO_esiB: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A0A0H2VDN9
GO_aroP: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P15993
GO_tnsB: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P13989
GO_xerC: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0A8P6
GO_asnC: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0ACI6
GO_puuP: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P76037
UP_esiB: https://www.uniprot.org/uniprot/A0A0H2VDN9
UP_aroP: https://www.uniprot.org/uniprot/P15993
UP_tnsB: https://www.uniprot.org/uniprot/P13989
UP_xerC: https://www.uniprot.org/uniprot/P0A8P6
UP_asnc: https://www.uniprot.org/uniprot/P0ACI6
UP_puuP: https://www.uniprot.org/uniprot/P76037
Ref1_esiB: https://pubmed.ncbi.nlm.nih.gov/23882011/
Ref1_tnsB: https://www.sciencedirect.com/science/article/pii/S1517838216305330
Ref1_xerC: https://www.mdpi.com/2079-6382/9/7/405
Ref2_xerC: https://aac.asm.org/content/54/6/2724
Ref1_puuP: https://link.springer.com/article/10.1007/s00726-013-1517-x
Ref2_puuP: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731653/
Genes | Antibiotic | Gene Ontology Annotations |
Mechanism of Action | References |
---|---|---|---|---|
aadB | Gentamicin Tobramycin Amikacin | GO_aadB | Antibiotic inactivation | CARD_aadB, Ref1_aadB, Ref2_aadB, Ref3_aadB, Ref4_aadB |
neo | Gentamicin Tobramycin Amikacin | GO_neo | Kanamycin kinase activity | - |
msr(E) | GO_msrE | Plasmid DNA | Ref1_msrE, Ref2_msrE, Ref3_msrE, Ref4_msrE | |
emrE | Gentamicin | GO_emrE | Antibiotic efflux | CARD_emrE |
cysL | Tobramycin | GO_cysL | DNA binding | - |
rmtB | Amikacin | GO_rmtB | Antibiotic target alteration | CARD_rmtB, Ref1_rmtB, Ref2_rmtB, Ref3_rmtB, Ref4_rmtB |
aadB (Gentamicin, Tobramycin and Amikacin)
aadB encodes for 2''-aminoglycoside nucleotidyltransferase (UP_aadB)
It helps in mediating bacterial resistance to kanamycin, gentamicin, dibekacin, sisomicin, and tobramycin by
adenylate the 2''-hydroxyl group of these antibiotics in K. pneumoniae (UP_Kp_aadB) and kanamycin, gentamicin,
and tobramycin in E. coli (UP_aadB).
GO Molecular function: Aminoglycoside 2''-nucleotidyltransferase activity, and Metal ion binding
GO Biological function: Response to antibiotic and Antibiotic resistance
Complete annotation: GO_aadB
aadB is a resistance-conferring gene which is confirmed by one of the most essential and relevant databases
i.e. The Comprehensive Antibiotic Resistance Database (CARD). It works by the mechanism of antibiotic
inactivation and confers resistance to aminoglycoside antibiotics (CARD_aadB).
The study conducted by Rizk et al. (Ref1_aadB) involves the collection of clinical samples of A. baumannii
strains from intensive care units (ICUs) patients with suspected hospital-acquired infections followed by
checking them for resistance to aminoglycoside antibiotics. The study concluded that the most common prevalent
resistant genes among A. baumannii resistance to aminoglycosides was aadB with a contribution towards
antibiotic resistance as high as 42%. Since this study involves strains taken from hospitals with suspected
infections, it makes it essential for our novel protein-based drug to be checked for its efficacy against
aadB.
As per the study by Anderson et al. (Ref2_aadB), in A. baumannii AB5075, a large plasmid (p1AB5075) carries
aadB, a 2″-nucleotidyltransferase that confers resistance to both tobramycin and gentamicin but not amikacin.
It is very important in the case of our machine learning approach since our approach ranks aadB as the most
important feature (gene/allele) in the case of Gentamicin and Tobramycin but not in the case of Amikacin.
The study conducted by Chan et al. (Ref3_aadB), found a novel antibiotic resistance island in A. baumannii by
analyzing genomes of several isolates collected from the US hospital system. They further concluded that after
sequencing the genomes to completion, they found tobramycin-resistance gene aadB.
Si-Tuan et al., (Ref4_aadB) characterized the genome of the A. baumannii strain DMS06669 which was isolated
from the sputum of a male patient with hospital-acquired pneumonia, and identified genes related to antibiotic
resistance. They find aadB which is majorly resistant to gentamicin, as one of the genes responsible for
conferring resistance in the strain.
Importance: These several studies make it very clear that aadB is an important gene especially considering
aminoglycoside antibiotics. Moreover, the presence of resistance by aadB to majorly gentamicin and tobramycin
but not amikacin further validates the effectiveness of our machine learning analysis as aadB was the top
feature in the first two antibiotics but not in the latter.
neo (Gentamicin, Tobramycin and Amikacin)
neo encodes Aminoglycoside 3'-phosphotransferase (UP_neo)
GO Molecular function: ATP binding, Kanamycin kinase activity
GO Biological function: Response to antibiotic and Antibiotic resistance
Complete GO annotation: GO_neo
It helps in providing resistance to kanamycin, neomycin, paromomycin, ribostamycin, butirosin, and gentamicin
B in the case of K. pneumoniae. This enzyme is encoded by the kanamycin and neomycin resistance transposon
Tn5. Tn5 was originally isolated from K.pneumoniae, but has been transferred to a number of bacteria including
E.coli. Since it has been transferred to E. coli, it is quite important to check for its relevance in the case
of A. baumannii.
Importance: There has been a lack of literature studies conducted for neo in the context of A. baumannii, but
it targets using protein pathway which is similar in mechanism to aminoglycoside antibiotics. Moreover, as
mentioned before, it would be interesting to check for its relevance in A. baumannii.
msr(E) (Gentamicin, Tobramycin and Amikacin)
msr(E) encodes for ABC-F type ribosomal protection protein (UP_msrE).
GO Molecular function: ATPase binding and ATP binding
Complete annotation: GO_msrE
msr(E) is a resistant conferring gene as per the Comprehensive Antibiotic Resistance Database (CARD) and
provides resistance through antibiotic target alteration (CARD_msrE). Furthermore, as per CARD, Msr(E) is an
ABC-F subfamily protein expressed to K. pneumoniae that confers resistance to erythromycin and streptogramin B
antibiotics. It is associated with plasmid DNA. It is also 100% identical to ABC-F type ribosomal protection
protein Msr(E) which is in multiple species. Since it is associated with plasmid DNA, it becomes an important
factor in horizontal transfer and dissemination of antibiotic resistance.
Blackwell and Hall (Ref1_msrE) find in their study that macrolide resistance genes msrE and mphE were present
in an 18.2-kb plasmid of A. baumannii isolate from Singapore which confers resistance to erythromycin and
tetracycline, both of which follow protein synthesis mechanism.
A study conducted by Karah et al. (Ref2_msrE) concluded that msr(E) is one of the resistance genes present in
clinical isolates of A. baumannii in Pakistan. The study by Kumburu et al. (Ref3_msrE) utilized Whole Genome
Sequencing (WGS) to identify resistance-conferring genes in MDR A. baumannii in Tanzania. They found several
antibiotic resistance genes some of which were present in chromosomes while some on plasmids. msr(E) was
detected as an antibiotic resistance gene that is present on plasmids and playing an important role in the
spreading of the resistance.
Similar to the case of aadB, the study conducted by Si-Tuan et al., (Ref4_aadB, Ref4_msrE) identified msr(E)
which is majorly resistant to streptogramin, which follows the similar mechanism as of aminoglycoside
antibiotics.
Importance: As shown by several studies, msr(E) is responsible for resistance to several antibiotics like
macrolide, streptogramin, etc, which follow a similar mechanism to those of aminoglycosides, it becomes
exciting and interesting to check for its relevance to Gentamicin, Tobramycin, and Amikacin.
emrE (Gentamicin)
emrE encodes for Multidrug transporter EmrE (UP_emrE).
GO Molecular function: Antiporter activity, Identical protein binding, etc.
GO Biological function: Cellular response to DNA damage stimulus, Response to drug, etc.
Complete GO annotation: GO_emrE
It is a multidrug efflux protein that confers resistance to a wide range of toxic compounds, including
ethidium, methyl viologen, acriflavine, tetraphenylphosphonium (TPP+), benzalkonium, propidium, dequalinium,
and the aminoglycoside antibiotics streptomycin and tobramycin (UP_emrE).
Further, as per the Comprehensive Antibiotic Resistance Database (CARD), EmrE is a small multidrug transporter
and works by antibiotic efflux mechanism to confer antibiotic resistance (CARD_emrE).
Importance: emrE is majorly found in P. aeruginosa and E. coli, which makes it quite interesting to check for
existence on A. baumannii genomes. Moreover, it has been shown to be causing resistance to Tobramycin while
our machine learning detected it to be an important gene in the case of Gentamicin, so it would also be
exciting to validate and confirm by wet-lab experiments.
cysL (Tobramycin)
cysL encodes for HTH-type transcriptional regulator CysL (UP_cysL).
GO Molecular function: DNA-binding transcription factor activity
GO Biological function: DNA-templated regulation of transcription
Complete GO annotation: GO_cysL
There is a lack of literature evidence in the case of cysL, but it has been identified as one of the topmost
features in the case of Tobramycin, and given the fact our machine learning has identified several genes
confirming to literature evidence, cysL is one of the novel genes uncovered by our algorithm responsible for
antibiotic resistance.
Importance: It would be interesting to check the relevance and importance of cysL in the context of A.
baumannii and our novel protein-based drug as well, as it has been detected as the topmost feature by machine
learning.
rmtB (Amikacin)
rmtB encodes for 16S rRNA (guanine(1405)-N(7))-methyltransferase (UP_rmtB).
GO Molecular function: rRNA methyltransferase activity
GO Biological function: Response to antibiotic and Antibiotic resistance
Complete GO annotation: GO_rmtB
rmtB encoding protein specifically methylated the N7 position of guanine 1405 in 16S rRNA, and conferring
resistance to various aminoglycosides (UP_rmtB).
It is a resistance gene as per the Comprehensive Antibiotic Resistance Database (CARD), which works with the
mechanism of antibiotic target alteration and belongs to the drug class of aminoglycoside antibiotics
(CARD_rmtB).
Tada et al. (Ref1_rmtB) conducted a study on strains of A. baumannii and P. aeruginosa isolated from patients
in intensive care units (ICUs) in two medical settings in Vietnam and out of which 71.3% strains were highly
resistant to amikacin and gentamicin. They further concluded that, 16S rRNA methylase RmtB was produced by 9
strains (of 101) of A. baumannii and 2 (of 15) strains of P. aeruginosa and 16S rRNA methylase producing
organism are emerging.
The study by Lee et al. (Ref2_rmtB) analyzed amikacin resistant strains of gram-negative bacteria in Korea and
concluded that armA and rmtB were genes predominantly responsible for the resistance.
Wachino et al. (Ref3_rmtB) and Wang et al. (Ref4_rmtB) concluded that 16S rRNA methylases, which lead to the
high-level resistance of various aminoglycosides, can easily transfer to other bacteria since their genes are
typically present on plasmids. The transfer of genes plays an important role in horizontal gene transfer and
the dissemination of antibiotic resistance.
Importance: Several studies have indicated the spread of aminoglycoside resistance in A. baumannii which is a
major cause of worry for the researchers. Since our novel drug is protein-based therapeutic, it becomes
apparent to test our drug for its efficacy against such antibiotic-resistant genes.
GO_aadB: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0AE04
GO_neo: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A0A086HV77
GO_msrE: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A5Y460
GO_emrE: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P23895
GO_cysL: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A0A0M3FB12
GO_rmtB: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=Q763K9
UP_aadB: https://www.uniprot.org/uniprot/P0AE04
UP_Kp_aadB: https://www.uniprot.org/uniprot/P0AE05
UP_neo: https://www.uniprot.org/uniprot/P00552
UP_msrE: https://www.uniprot.org/uniprot/A5Y460
UP_emrE: https://www.uniprot.org/uniprot/P23895
UP_cysL: https://www.uniprot.org/uniprot/A0A0M3FB12
UP_rmtB: https://www.uniprot.org/uniprot/Q763K9
CARD_aadB: https://card.mcmaster.ca/ontology/36369
CARD_emrE: https://card.mcmaster.ca/ontology/36403
CARD_rmtB: https://card.mcmaster.ca/ontology/37240
Ref1_aadB: https://www.clin-lab-publications.com/article/3088
Ref2_aadB: https://msphere.asm.org/content/3/4/e00271-18
Ref3_aadB: https://academic.oup.com/jac/article-abstract/75/10/2760/5873331?redirectedFrom=fulltext
Ref4_aadB: https://ann-clinmicrob.biomedcentral.com/articles/10.1186/s12941-017-0250-9
Ref1_msrE: https://aac.asm.org/content/61/8/e00780-17
Ref2_msrE: https://ann-clinmicrob.biomedcentral.com/articles/10.1186/s12941-019-0344-7
Ref3_msrE: https://academic.oup.com/jac/article/74/6/1484/5370329
Ref4_msrE: https://ann-clinmicrob.biomedcentral.com/articles/10.1186/s12941-017-0250-9
Ref1_rmtB: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680199/
Ref2_rmtB: https://www.jkms.org/Synapse/Data/PDFData/0063JKMS/jkms-33-e262.pdf
Ref3_rmtB: https://pubmed.ncbi.nlm.nih.gov/17875999/
Ref4_rmtB: https://www.spandidos-publications.com/10.3892/etm.2016.3828#b13-etm-0-0-3828
Genes | Antibiotic | Gene Ontology Annotations |
Mechanism of Action | References |
---|---|---|---|---|
glmM | Ceftriaxone | GO_glmM | Phosphoglucosamine mutase protein | Ref1_glmM, Ref2_glmM, Ref3_glmM |
mshA | Ceftriaxone | GO_mshA | D-inositol 3-phosphate glycosyltransferase | CARD1_mshA, CARD2_mshA, CARD3_mshA |
relE | Imipenem | GO_relE | mRNA interferase toxin | Ref1_relE, Ref2_relE, CARD_relE |
tufA | Imipenem | GO_tufA | Elongation factor Tu 1 | - |
yafQ | Ceftazidime | GO_yafQ | mRNA interferase toxin | - |
eptA | Ceftazidime | GO_eptA | Phosphoethanolamine transferase | Ref1_eptA, Ref2_eptA, CARD_eptA |
glmM (Ceftriaxone)
glmM encodes for Phosphoglucosamine mutase protein (UP_glmM).
GO Molecular function: Magnesium ion binding, Phosphoglucosamine mutase activity, and Phosphomannomutase
activity
GO Biological function: Carbohydrate metabolic process, Protein autophosphorylation, and
UDP-N-acetylglucosamine biosynthetic process
Complete GO annotation: GO_glmM
Li et al. (Ref1_glmM) analyzed carbapenem-resistant clinical A. baumannii strains. They identified several
AbaR resistance islands for a better understanding of evolutionary processes contributing to the emergence of
carbapenem-resistant A. baumannii. As per their analysis, phosphoglucosamine mutase (GlmM) was detected in
type 2, 7, and 10 AbaR islands. It is important to note that GlmM can catalyze the conversion of
glucosamine-6-phosphate to glucosamine-1-phosphate, which is an essential step in the formation of the cell
wall precursor UDP-N-acetylglucosamine (Ref2_glmM).
Kenyon and Lee (Ref3_glmM) analyzed the biosynthesis of extracellular polysaccharides which are major
immunogenic components of the bacterial cell envelope. They further mentioned that GlmM is required for the
synthesis of UDP-D-GlcpNAc.
Importance: There are several studies stating that glmM encodes for the formation of cell wall precursors, and
it has been detected as one of the top features in the case of Ceftriaxone which also works with the mechanism
of bacterial cell wall synthesis. So, our machine learning algorithm has identified genes involved in the
pathway of antibiotics.
mshA (Ceftriaxone)
mshA encodes for D-inositol 3-phosphate glycosyltransferase (UP_mshA).
GO Molecular function: Acetylglucosaminyltransferase activity, transferring glycosyl groups
GO Biological function: Mycothiol biosynthetic process
Complete annotation: GO_mshA
It is involved in the mechanism of Acetylglucosaminyltransferase which is important for cell wall mechanism as
mentioned in the case of glmM.
The Comprehensive Antibiotic Resistance Database (CARD) provides several evidences for the involvement of mshA
in antibiotics targeting cell wall mechanisms. Mutations in mshA result in the inactivation of antibiotics and
it works by the mechanism of antibiotic target alteration (CARD1_mshA).
As mentioned above, mshA is glycosyltransferase and is involved in the first step of mycothiol biosynthesis.
This is a step that is required for growth in M. tuberculosis and resistance has been in the gene to
isoniazid, which is antibiotic inhibiting mycobacterial cell wall (CARD2_mshA). Further, the mutations in mshA
confer resistance to isoniazid in M. tuberculosis (CARD3_mshA).
Importance: Our machine learning approach identifies allele of mshA as one of the most important features in
predicting resistance phenotype of strain, which in accordance with literature evidence related to mutations
in mshA causing antibiotic resistance. Moreover, it has been detected as one of the most important genes in
the case of Ceftriaxone, which also works with mechanisms of bacterial cell wall synthesis.
relE (Imipenem)
relE encodes for mRNA interferase toxin RelE (UP_relE).
GO Molecular function: DNA-binding transcription repressor activity, ribosome binding, rRNA binding
GO Biological function: Cellular response to amino acid starvation, mRNA catabolic process, negative
regulation of translation
GO Cellular component: Protein-DNA complex
Complete GO annotation: GO_relE
relE encodes for mRNA interferase, and mRNA interferases play a role in bacterial persistence to antibiotics;
overexpression of this protein induces persisters resistant to ciprofloxacin and ampicillin (UP_relE,
Ref1_relE).
relE is a part of type II toxin-antitoxin system relBE wherein it is toxin and relB is anti-toxin. In presence
of unfavorable conditions, toxin relE sharply increases persisters (cells that neither grow nor die in the
presence of bactericidal agents) and are largely responsible for high levels of biofilm tolerance to
antimicrobials (CARD_relE). So it blocks the process of mRNA to protein conversion inhibiting cell growth. The
increase in biofilm tolerance makes it difficult for antibiotics to reach the bacteria for necessary action.
Pourhajibagher et al. (Ref2_relE) utilized the concept of this toxin-antitoxin system, relBE, for designing
Antimicrobial Photodynamic Therapy as an alternative to conventional antibiotic therapy using in-silico
modeling and bioinformatics analysis.
Importance: There are several studies indicating the involvement of relE in being responsible for antibiotic
resistance, so it makes it interesting to look for its relevance in the case of A. baumannii using wet-lab
experiments.
tufA (Imipenem)
tufA encodes for the Elongation factor Tu 1 (UP_tufA).
GO Molecular function: GTPase activity, GTP binding
GO Biological function: Translational elongation, Response to antibiotic and Antibiotic Resistance.
Complet GO annotation: GO_tufA
The study conducted by Koenigs et al. (Ref1_tufA) showed for the first time that A. baumannii binds to
host-derived plasminogen with help of the translation elongation factor Tuf as a moonlighting
plasminogen-binding protein that is exposed on the outer surface of A. baumannii. This binding phenomenon is
at least partly dependent on lysine residues and ionic interactions. Once bound to Tuf, plasminogen can be
converted to active plasmin and proteolytically degrade fibrinogen as well as the key complement component
C3b. Therefore they concluded that Tuf acts as a multifunctional protein that may contribute to the virulence
of A. baumannii by aiding in dissemination and evasion of the complement system.
Importance: The results of the above study clearly indicates the importance of Tuf protein is increasing and
contributing to the virulence of A. baumannii. It would be interesting to explore more about the functioning
and mechanism of this protein in the context of our novel protein-based drug-using wet-lab experiments.
yafQ (Ceftazidime)
yafQ encodes for mRNA interferase toxin YafQ (UP_yafQ)
GO Molecular function: DNA binding, ribosome binding
GO Biological function: mRNA catabolic process, response to antibiotic
Complete GO annotation: GO_yafQ
yafQ is working in a similar mechanism that of relE i.e. working as a toxin-antitoxin pair. YafQ protein pairs
with DinJ. which seems to play a role in biofilm formation. mRNA interferases play a role in bacterial
persistence to antibiotics (UP_yafQ). Since it helps in biofilm formation and biofilm can decrease the amount
of antibiotics reaching the bacterial cell, therefore it is indirectly responsible for increasing antibiotic
resistance.
Importance: It has not been explored much in the literature, and it would be really interesting to explore its
working in the context of A. baumannii along with relE as well.
eptA (Ceftazidime)
eptA encodes Phosphoethanolamine transferase EptA (UP_eptA).
GO Molecular function: phosphotransferase activity, sulfuric ester hydrolase activity
GO Biological function: Lipid A biosynthesis, Antibiotic Resistance
Complete GO annotation: GO_eptA
As per the Comprehensive Antibiotic Resistance Database (CARD), eptA mediates the modification Lipid A by the
addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosphoethanolamine which results in a less negative
cell membrane and decreased binding of polymyxin B. It works by the mechanism of antibiotic target alteration
(CARD_eptA).
The study conducted by Gerson et al. (Ref1_eptA) concluded that mutations in eptA were associated with
colistin resistance in A. baumannii. Trebsoc et al. (Ref2_eptA) suggested that direct targeting of the
homologous PetN transferases PmrC/EptA may have the potential to overcome colistin resistance in A. baumannii.
Importance: eptA has been known to provide resistance to polymyxin B which works with the mechanism of
membrane disruption. It has been identified as one of the top genes for Ceftazidime which also works with the
mechanism of cell wall synthesis. Further, it has been studied to play a role in colistin resistance which
makes it very important and interesting to check for the efficacy of our novel protein-based drug against
eptA.
GO_glmM: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P31120
GO_mshA: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P9WMY7
GO_relE: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0C077
GO_tufA: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0CE47
GO_yafQ: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=Q47149
GO_aptA: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P30845
UP_glmM: https://www.uniprot.org/uniprot/P31120
UP_mshA: https://www.uniprot.org/uniprot/P9WMY7
UP_relE: https://www.uniprot.org/uniprot/P0C077
UP_tufA: https://www.uniprot.org/uniprot/P0CE47
UP_yafQ: https://www.uniprot.org/uniprot/Q47149
UP_eptA: https://www.uniprot.org/uniprot/P30845
CARD1_mshA: https://card.mcmaster.ca/ontology/43086
CARD2_mshA: https://card.mcmaster.ca/ontology/43087
CARD3_mshA: https://card.mcmaster.ca/ontology/43111
CARD_relE: https://card.mcmaster.ca/ontology/40753
CARD_eptA: https://card.mcmaster.ca/ontology/40186
Ref1_glmM: https://aac.asm.org/content/59/2/1168
Ref2_glmM: https://pubmed.ncbi.nlm.nih.gov/10913078/
Ref3_glmM: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628348/
Ref1_relE: https://pubmed.ncbi.nlm.nih.gov/21788497/
Ref2_relE: https://www.derpharmachemica.com/pharma-chemica/in-silico-modeling-of-releb-type-ii-toxinantitoxin-system-in-acinetobacter-baumannii-as-a-therapeutic-target-via-antimicrobial-pho-14977.html
Ref1_eptA: https://aac.asm.org/content/63/3/e01586-18
Ref2_eptA: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635527/
Mechanism: Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with
para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic
acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. So, in a nutshell,
combinations of these drugs mainly work with folate synthesis.
In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthase
(DHPS), an enzyme involved in folate synthesis.
folP
folP encodes for Dihydropteroate synthase (UP_folP)
GO Molecular function: Dihydropteroate synthase activity, and metal ion binding
GO Biological function: Folate biosynthesis and Response to drug
GO Cellular component: Cytoplasm and Cytosol
Complete GO annotation: GO_folP
The protein Dihydropteroate synthase catalyzes the condensation of para-aminobenzoate (PABA) with
6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-dihydropteroate (H2Pte), the immediate
precursor of folate derivatives (UP_folP).
As per the Comprehensive Antibiotic Resistance Database (CARD), point mutations in dihydropteroate synthase,
folP prevent sulfonamide antibiotics from inhibiting its role in folate synthesis, thus conferring sulfonamide
resistance (CARD_folP). It works with the mechanism of antibiotic target alteration. Our machine learning
approach identified folP and its alleles as the topmost important features which further validate the efficacy
of our algorithm.
Importance: The detection of folP in the case of antibiotics working with folate disruption by machine
learning algorithm is a very important indication for the efficacy of the approach. It would be very
interesting to check for the impact of folP in establishing resistance to our novel protein-based drug.
Mechanism: Ampicillin/sulbactam is a combination of a β-lactam antibiotic and a β-lactamase inhibitor.
Ampicillin works by binding to penicillin-binding proteins (PBPs) to inhibit bacterial cell wall synthesis.
Sulbactam blocks the enzyme which breaks down ampicillin and thereby allows ampicillin to attack and kill the
bacteria.
Beta-lactam enzymes are produced by some bacteria that are responsible for their resistance to beta-lactam
antibiotics like penicillins, cephalosporins, cephamycins, and carbapenems. These antibiotics have a common
element in their molecular structure: a four-atom ring known as a beta-lactam.
bla
bla encodes for Beta-lactamase TEM
GO Molecular function: Beta-lactamase activity
GO Biological function: Beta-lactam antibiotic catabolic process, response to antibiotic and Antibiotic
resistance
Complete GO annotation: GO_bla
TEM-type is the most prevalent beta-lactamases in Enterobacteriaceae; they hydrolyze the beta-lactam bond in
susceptible beta-lactam antibiotics, thus conferring resistance to these antibiotics (UP_bla).
The study conducted by Subramaniyan and Sundaram (Ref1_bla) concluded the presence of bla genes in
carbapenem-resistant P. aeruginosa and A. baumannii isolated from clinical settings, Intensive Care Unit
(ICU). Further, the study by Kumar et al. (Ref2_bla) analyzed the carbapenem-resistant A. baumannii isolates
from two tertiary care hospitals of North India and concluded that bla encoding clones. It is an important
discovery especially in the context of India hospital settings.
Importance: Our machine learning algorithm identifies bla as the most important feature, which is also in the
mechanism of Ampicillin and Sulbactam. It shows the efficacy of our approach. Moreover, the above studies
clearly indicate the importance of bla gene in A. baumannii and it would be surely interesting to check for
its relevance in the case of our novel protein-based drug.
GO_folP: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P0AC13
GO_bla: https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=P62593
UP_folP: https://www.uniprot.org/uniprot/P0AC13
UP_bla: https://www.uniprot.org/uniprot/P62593
CARD_folP: https://card.mcmaster.ca/ontology/36365
Ref1_bla: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896190/
Ref2_bla: https://pubmed.ncbi.nlm.nih.gov/31362071/
Correlation and mutational analysis of gene-gene pair
xerC vs. ssuC (Ciprofloxacin)
- Resistance increases with mutations in xerC
- Resistance increases with mutations in ssuC
- The increase in resistance with mutations in both genes confirm a positive correlation between them
- Mutations in xerC are accompanied by an increase in resistance for all of the following, ssuC_1, ssuC_2, ssuC_3, ssuC_4 and ssuC_5
puuP vs. astC (Levofloxacin)
- astC is a gene important for resistance but strains became more susceptible in presence of puuP
- Mutations in astC causes a decrease in resistance
- Mutations in astC increase resistance in presence of puuP but decrease resistance with mutations in puuP which confirms a negative correlation
emrE vs. folP (Gentamicin)
- Resistance increases with mutations in emrE
- Resistance increases with mutations in folP
- Mutations in both the genes work in tandem and increase the resistance of strains confirming a positive correlation between them
cysL vs. hcaR (Tobramycin)
- Resistance increases with mutations in cysL
- Resistance decreases with mutations in hcaR
- Mutations in hcaR increases the resistance but not when cysL is present confirming a negative correlation
esiB vs. cspV (Amikacin)
- Resistance decreases with mutations in esiB
- Resistance decreases with mutations in cspV
- Resistance in strains with cspV decreases or reaches zero with mutations in esiB confirming a positive correlation
ssuA vs. ssuC (Ceftriaxone)
- There is lack of strains having ssuA and ssuC genes without mutations
- Resistance increases with mutations in ssuA
- Resistance increases with mutations in ssuC which confirms a positive correlation between genes
tufA vs. tufB (Imipenem)
- Resistance decreases with mutations in tufA
- Resistance increases with mutations in tufB confirming a negative correlation between genes
aphA vs. fatA (Ceftazidime)
- Resistance increases with mutations in aphA
- Resistance increases with mutations in fatA which confirms a positive correlation between genes
- There is less number of strains having fatA gene and much more number of strains with mutations in fatA
folP vs. emrE
- Resistance increases with mutations in folP
- Resistance increases with mutations in emrE confirming a positive correlation between genes
- There is less number of strains with folP and more number of strains with mutations in folP
mobA vs. yddG
- Resistance decreases with mutations in mobA
- Resistance increases with mutations in yddG confirming a negative correlation between genes
- Increased resistance due to mutations in yddG vanished with mutations in mobA