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

Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008.
Bioinformation (Impact Factor: 0.5). 02/2013; 9(4):174-81. DOI: 10.6026/97320630009174
Source: PubMed

ABSTRACT Unlabelled:
: 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.

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

Download full-text


Available from: Rakesh Joshi, Mar 29, 2014
1 Follower
50 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bacillus mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis and H37Rv is the most studied strain. Identification of new drug targets for Mtb is among one of the priorities since it is still a major global health problem by being a cause of morbidity and mortality for millions of people each year. We used centrality measures to identify the most central proteins from protein-protein interaction network of mycobacterium tuberculosis H37Rv which was retrieved from STRING database by hypothesising these proteins would be important to alter the function of the network. We then refined the result by using a dataset obtained from Drug Target Protein Database to identify non-human homologous proteins since in host-parasite diseases like tuberculosis; non-homologous proteins (enzymes) as drug target are the primary choices. We also tried to compare our proposed potential non-human homologous protein target lists against previously reported targets. Moreover, the structural coverage of the proposed target list has been identified. The analysis shows that 807 proteins in mycobacterium tuberculosis H37Rv were found at the centre of gravity of the functional network of which 390 were non-human homologous, which are thought to be potential drug targets. 119 (30.51%) of the 390 proteins were reported as drug targets and only 33 (8.46%) of the non-human homologous proposed target lists have solved structure.
    Journal of Theoretical Biology 08/2014; 361. DOI:10.1016/j.jtbi.2014.07.031 · 2.12 Impact Factor