Resistome analysis of Mycobacterium tuberculosis: Identification of aminoglycoside 2'-Nacetyltransferase (AAC) as co-target for drug desigining |
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Authors: | Rakesh S Joshi Mahendra D Jamdhade Mahesh S Sonawane Ashok P Giri |
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Institution: | 1Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008;2National Centre for Cell Science, University of Pune Campus, Ganeshkhind Road, Pune 411007 |
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Abstract: | The emergence of multidrug resistant tuberculosis (MDRTB) highlights the urgent need to understand the mechanisms of
resistance to the drugs and to develop a new arena of therapeutics to treat the disease. Ethambutol, isonazid, pyrazinamide,
rifampicin are first line of drugs against TB, whereas aminoglycoside, polypeptides, fluoroquinolone, ethionamide are important
second line of bactericidal drugs used to treat MDRTB, and resistance to one or both of these drugs are defining characteristic of
extensively drug resistant TB. We retrieved 1,221 resistant genes from Antibiotic Resistance Gene Database (ARDB), which are
responsible for resistance against first and second line antibiotics used in treatment of Mycobacterium tuberculosis infection. From
network analysis of these resistance genes, 53 genes were found to be common. Phylogenetic analysis shows that more than 60% of
these genes code for acetyltransferase. Acetyltransferases detoxify antibiotics by acetylation, this mechanism plays central role in
antibiotic resistance. Seven acetyltransferase (AT-1 to AT-7) were selected from phylogenetic analysis. Structural alignment shows
that these acetyltransferases share common ancestral core, which can be used as a template for structure based drug designing.
From STRING analysis it is found that acetyltransferase interact with 10 different proteins and it shows that, all these interaction
were specific to M. tuberculosis. These results have important implications in designing new therapeutic strategies with
acetyltransferase as lead co-target to combat against MDR as well as Extreme drug resistant (XDR) tuberculosis.AbbreviationsAA - amino acid,
AT - Acetyltransferase,
AAC - Aminoglycoside 2''-N-acetyltransferase,
XDR - Extreme drug-resistant,
MDR - Multidrug-resistant,
Mtb - Mycobacterium tuberculosis,
TB - Tuberculosis. |
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Keywords: | Antibiotic resistance Mycobacterium tuberculosis Acetyltransferase Network analysis |
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