The Isoniazid Paradigm of Killing, Resistance, and Persistence in Mycobacterium tuberculosis

Abstract

Isoniazid (INH) was the first synthesized drug that mediated bactericidal killing of the bacterium Mycobacterium tuberculosis, a major clinical breakthrough. To this day, INH remains a cornerstone of modern tuberculosis (TB) chemotherapy. This review describes the serendipitous discovery of INH, its effectiveness on TB patients, and early studies to discover its mechanisms of bacteriocidal activity. Forty years after its introduction as a TB drug, the development of gene transfer in mycobacteria enabled the discovery of the genes encoding INH resistance, namely, the activator (katG) and the target (inhA) of INH. Further biochemical and x-ray crystallography studies on KatG and InhA proteins and mutants provided comprehensive understanding of INH mode of action and resistance mechanisms. Bacterial cultures can harbor subpopulations that are genetically or phenotypically resistant cells, the latter known as persisters. Treatment of exponentially growing cultures of M. tuberculosis with INH reproducibly kills 99% to 99.9% of cells in 3 days. Importantly, the surviving cells are slowly replicating or non-replicating cells expressing a unique stress response signature: these are the persisters. These persisters can be visualized using dual-reporter mycobacteriophages and their formation prevented using reducing compounds, such as N-acetylcysteine or vitamin C, that enhance M. tuberculosis’ respiration. Altogether, this review portrays a detailed molecular analysis of INH killing and resistance mechanisms including persistence. The phenomenon of persistence is clearly the single greatest impediment to TB control, and research aimed at understanding persistence will provide new strategies to improve TB chemotherapy.

Hydrothermal Synthesize of HF-Free MIL-100(Fe) for Isoniazid-Drug Delivery

“…Long-period treatment accompanied by consumption can cause hepatotoxicity and peripheral neuritis, as well as the emergence of drug-resistant species 4–6 . The long duration of TB treatment is due to the poor solubility and bioavailability of the INH 7,8 ; the controlled drug delivery is one of the strategies to overcome these drawbacks.…”

Genotypic Characterization of katG, inhA, and ahpC in Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates in Shanghai, China

“…Until today, INH is still the cornerstone of modern tuberculosis chemotherapy. However, M. tuberculosis is becoming more resistant to INH (4). A variety of genes are involved in M. tuberculosis resistance to INH.…”

Molecular Detection of Isoniazid and Rifampin Resistance in Mycobacterium tuberculosis Isolates from Lorestan Province, Iran from 2014 to 2017

“…Isoniazid (INH) is a prodrug and a catalase-peroxidase encoded by katG gene, associated with peroxidase activ-ity, activates it to be converted to a toxic substance that affects mycolic acid biosynthesis (7). Between 40% and 95% of INH resistant clinical MTB isolates have mutations in katG gene, 75% to 90% of which are located in codon315, with 10% to 25% of mutations located in other katG loci (8).…”