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

The emergence of multidrug resistant tuberculosis (MDRTB) highlights the urgent need to understand the mechanisms ofresistance 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 importantsecond line of bactericidal drugs used to treat MDRTB, and resistance to one or both of these drugs are defining characteristic ofextensively drug resistant TB. We retrieved 1,221 resistant genes from Antibiotic Resistance Gene Database (ARDB), which areresponsible for resistance against first and second line antibiotics used in treatment of Mycobacterium tuberculosis infection. Fromnetwork analysis of these resistance genes, 53 genes were found to be common. Phylogenetic analysis shows that more than 60% ofthese genes code for acetyltransferase. Acetyltransferases detoxify antibiotics by acetylation, this mechanism plays central role inantibiotic resistance. Seven acetyltransferase (AT-1 to AT-7) were selected from phylogenetic analysis. Structural alignment showsthat 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 interactionwere specific to M. tuberculosis. These results have important implications in designing new therapeutic strategies withacetyltransferase as lead co-target to combat against MDR as well as Extreme drug resistant (XDR) tuberculosis.

Abbreviations

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