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Title

Resistome analysis of Mycobacterium tuberculosis: Identification of aminoglycoside 2-N-acetyltransferase (AAC) as co-target for drug desigining

 

Authors

Rakesh S Joshi1*, Mahendra D Jamdhade2, Mahesh S Sonawane2 & Ashok P Giri1

 

Affiliation

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

 

Email

rs.joshi@ncl.res.in; *Corresponding author

 

Article Type

Hypothesis

 

Date

Received December 08, 2012; Accepted December 20, 2012; Published February 21, 2013

 

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.  

 

Keywords

Antibiotic resistance, Mycobacterium tuberculosis, Acetyltransferase, Network analysis.

 

Abbreviations

AA-amino acid, AT-Acetyltransferase, AAC-Aminoglycoside 2'-N-acetyltransferase, XDR-Extreme drug-resistant, MDR-Multidrug-resistant, Mtb-Mycobacterium tuberculosis, TB-Tuberculosis.

 

Citation

Joshi et al.   Bioinformation 9(4): 174-181 (2013)

 

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.