Molecular modelling and docking analysis of katG and rpoB gene in MDR-TB isolates from North Central Indian population

Tuberculosis caused by Mycobacterium tuberculosis, requires multi drug therapy approach. Drug resistance in M. tuberculosis is caused by mutations in specific regions in drug target genes. The study aimed to identify mutations in katG and rpoB genes and investigate the drug–drug target interactions. A total of 27 MDR-TB isolates were sequenced for katG and rpoB genes and docking and MIC analysis were performed. Three types of mutations for katG gene (Arg463Leu in all isolates of Sahariya and non-tribes; Asp529Thr and Asp529His, each in two isolates only, in Sahariya) were observed. In rpoB gene, the Ser531Leu change was observed in 17/21 isolates in Sahariya and 3/6 isolates in non-tribes. The docking analysis revealed that the drugs isoniazid and rifampicin bind to different residues in mutant forms than their proposed active sites, making active binding sites rigid and causing resistance. The MIC for isoniazid was found to range from 0.2 to 5 μg/ml in Sahariya tribe, whereas, in non-tribes, it is 0.2 μg/ml and 1 μg/ml. The MIC for rifampicin was observed at 64 μg/ml in both the population groups. The study explored the possible functional variation in isoniazid and rifampicin resistance with respect to the identified mutations. The present results indicate that these mutations affect the drug binding affinity and are causing resistance.