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

Research output: Contribution to journalReview article

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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.

Original languageEnglish (US)
Pages (from-to)3450-3461
Number of pages12
JournalJournal of Molecular Biology
Volume431
Issue number18
DOIs
StatePublished - Aug 23 2019

Fingerprint

Isoniazid
Mycobacterium tuberculosis
Tuberculosis
Mycobacteriophages
Drug Therapy
Crystallography
Acetylcysteine
Genetic Association Studies
Mutant Proteins
Mycobacterium
Pharmaceutical Preparations
Ascorbic Acid
Respiration
X-Rays
Bacteria
Research
Genes

Keywords

  • isoniazid
  • mechanism
  • mycobacteriophage
  • persister

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

The Isoniazid Paradigm of Killing, Resistance, and Persistence in Mycobacterium tuberculosis. / Vilchèze, Catherine; Jacobs, William R.

In: Journal of Molecular Biology, Vol. 431, No. 18, 23.08.2019, p. 3450-3461.

Research output: Contribution to journalReview article

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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.",
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