Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis.
Isoniazid (INH) is one of the most active compounds used to treat tuberculosis (TB) worldwide. In addition, INH has been used as a prophylactic drug for individuals with latent Mycobacterium tuberculosis (MTB) infection to prevent reactivation of disease. Importantly, the definition of multidrug resistance (MDR) in TB is based on the resistance of MTB strains to INH and rifampicin (RIF). Despite its simple chemical structure, the mechanism of action of INH is very complex and involves several different concepts. Many pathways pertaining to macromolecular synthesis are affected, notably mycolic acid synthesis. The pro-drug INH is activated by catalase-peroxidase (KatG), and the active INH products are targeted by enzymes namely, enoyl acyl carrier protein (ACP) reductase (InhA) and beta-ketoacyl ACP synthase (KasA). In contrast, INH is inactivated by arylamine N-acetyltransferases (NATs). Consequently, the molecular mechanisms of INH resistance involve several genes in multiple biosynthetic networks and pathways. Mutation in the katG gene is the major cause for INH resistance, followed by inhA, ahpC, kasA, ndh, iniABC,fadE, furA, Rv1592c and Rv1772. The recent association of efflux genes with INH resistance has also gained considerable attention. Interestingly, substitutions have also been observed in nat, fabD, and accD recently in resistant isolates. Understanding the mechanisms operating behind INH action and resistance would enable better detection of INH resistance. This information would aid novel drug design strategies. Herein we review all mechanisms known to potentially contribute to the complexity of INH action and mechanisms of resistance in MTB, with insights into methods for detection of INH resistance as well as their limitations.
Centre for Biomedical Informatics, National Institute for Research in Tuberculosis, India. Electronic address: nusrath.a@nirt.res.in.
Ameeruddin Nusrath
AN
Unissa
Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute (PHRI) at Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ, USA.
Selvakumar
S
Subbian
Centre for Biomedical Informatics, National Institute for Research in Tuberculosis, India.
Luke Elizabeth
LE
Hanna
Division of Mycobacteriology, National Institute for Research in Tuberculosis, India.
Nagamiah
N
Selvakumar
D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D014376:Tuberculosis / Q000382:microbiology*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D007538:Isoniazid
Drug resistance mechanisms; INH; KatG; Mode of action; Mycobacterium tuberculosis; S315T