Identification and Characterization of Genetic Determinants of Isoniazid and Rifampicin Resistance in Mycobacterium tuberculosis in Southern India

• Published in: Scientific reports Vol. 9; no. 1; pp. 10283 - 13
• Main Authors: Munir, Asma, Kumar, Narender, Ramalingam, Suresh Babu, Tamilzhalagan, Sembulingam, Shanmugam, Siva Kumar, Palaniappan, Alangudi Natarajan, Nair, Dina, Priyadarshini, Padma, Natarajan, Mohan, Tripathy, Srikanth, Ranganathan, Uma Devi, Peacock, Sharon J., Parkhill, Julian, Blundell, Tom L., Malhotra, Sony
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-07-2019; Nature Publishing Group
• Subjects: 45; 631/114/2410; 631/208/737; 631/535/1267; Adult; Allosteric properties; Allosteric Regulation - drug effects; Antitubercular Agents - pharmacology; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Catalase - chemistry; Catalase - genetics; Catalase - metabolism; DNA-Directed RNA Polymerases - chemistry; DNA-Directed RNA Polymerases - genetics; DNA-Directed RNA Polymerases - metabolism; Drug development; Drug resistance; Drug Resistance, Bacterial; Genetic analysis; Genomes; Humanities and Social Sciences; Humans; India; Isoniazid; Isoniazid - pharmacology; Learning algorithms; Machine Learning; Models, Molecular; multidisciplinary; Mutation; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - growth & development; Nucleotide sequence; Protein Conformation; Protein interaction; Protein Stability - drug effects; Proteins; Rifampin; Rifampin - pharmacology; RpoB protein; Science; Science (multidisciplinary); Tuberculosis; Tuberculosis - drug therapy; Tuberculosis - microbiology; Whole Genome Sequencing; India
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-46756-x

Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of
Mycobacterium tuberculosis
. There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical
M. tuberculosis
isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in
katG
and S450L in
rpoB
respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface.