Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis

• Published in: Infection, genetics and evolution genetics and evolution, 2016-11, Vol.45, p.474-492
• Main Authors: Unissa, Ameeruddin Nusrath, Subbian, Selvakumar, Hanna, Luke Elizabeth, Selvakumar, Nagamiah
• Format: Article
• Language: English
• Subjects: Antitubercular Agents - pharmacology; Bacterial Proteins - genetics; Drug resistance mechanisms; Drug Resistance, Bacterial - genetics; Humans; INH; Isoniazid - pharmacology; KatG; Mode of action; Mutation - genetics; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; S315T; Tuberculosis - microbiology
• ISSN: 1567-1348; 1567-7257
• DOI: 10.1016/j.meegid.2016.09.004

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. •Isoniazid (INH) is one of the most active compounds used to treat and prevent worldwide.•Despite its simple structure, the mechanism of action of INH is very complex and involves several different concepts.•Similarly, the molecular basis of resistance to INH involves various genes in multiple biosynthetic networks and pathways.•This review focuses on mechanisms that are responsible for the complex nature of INH action and resistance.