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.
Highlights
Tuberculosis (TB), a bacterial origin infectious disease caused by obligate human pathogen Mycobacterium tuberculosis (Mtb)
Sequence analysis and Phylogenetic analysis The protein sequences that are found to be common through network analysis from M. tuberculosis H37Rv and other Mycobacterium species were retrieved from NCBI
Homology modeling and structural comparison Seven different Aminoglycoside 2’-N-acetyltransferase (AAC) (AT-1 to -7) from different clads were selected and amino acid sequence analysis was done by performing a multiple sequence alignment using ClustalX and conserved sequences and motifs were identified using PSI-BLAST search [28, 29] and Pfam database [30]
Summary
Tuberculosis (TB), a bacterial origin infectious disease caused by obligate human pathogen Mycobacterium tuberculosis (Mtb). To counter the drug resistance in Mtb, global efforts are on to explore novel strategies for drug development and search for new therapeutic molecules as a drug target Methods such as rotations of antibiotic combinations, improved medical surveillance to ensure proper patient compliance towards drug therapy are proving less useful compared to speed with which pathogen is becoming resistant to drugs. We use wide-scale network and phylogenetic analysis of genes and proteins association to discover possible new target to combat against MDR-TB and XDR-TB. Homology modeling and structural comparison Seven different Aminoglycoside 2’-N-acetyltransferase (AAC) (AT-1 to -7) from different clads were selected and amino acid sequence analysis was done by performing a multiple sequence alignment using ClustalX and conserved sequences and motifs were identified using PSI-BLAST search [28, 29] and Pfam database [30]. Ramchandran plots of the amino acid residues in the allowed predicting model quality. region and consider the overall G -factors to give scores for open access
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