Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis

Catherine Vilchèze, Travis Hartman, Brian Weinrick, Paras Jain, Torin R. Weisbrod, Lawrence W. Leung, Joel S. Freundlich, William R. Jacobs

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Persistence, manifested as drug tolerance, represents a significant obstacle to global tuberculosis control. The bactericidal drugs isoniazid and rifampicin kill greater than 99% of exponentially growing Mycobacterium tuberculosis (Mtb) cells, but the remaining cells are persisters, cells with decreased metabolic rate, refractory to killing by these drugs, and able to generate drug-resistant mutants. We discovered that the combination of cysteine or other small thiols with either isoniazid or rifampicin prevents the formation of drug-tolerant and drug-resistant cells in Mtb cultures. This effect was concentrationand time-dependent, relying on increased oxygen consumption that triggered enhanced production of reactive oxygen species. In infected murine macrophages, the addition of N-acetylcysteine to isoniazid treatment potentiated the killing of Mtb. Furthermore, we demonstrate that the addition of small thiols to Mtb drug treatment shifted the menaquinol/menaquinone balance toward a reduced state that stimulates Mtb respiration and converts persister cells to metabolically active cells. This prevention of both persister cell formation and drug resistance leads ultimately to mycobacterial cell death. Strategies to enhance respiration and initiate oxidative damage should improve tuberculosis chemotherapies.

Original languageEnglish (US)
Pages (from-to)4495-4500
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number17
DOIs
StatePublished - Apr 25 2017

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Drug Tolerance
Mycobacterium tuberculosis
Drug Resistance
Respiration
Isoniazid
Pharmaceutical Preparations
Rifampin
Sulfhydryl Compounds
Tuberculosis
Vitamin K 2
Acetylcysteine
Oxygen Consumption
Cysteine
Reactive Oxygen Species
Cell Death
Macrophages
Drug Therapy
Therapeutics

Keywords

  • Drug resistance
  • Mycobacterial persister
  • Oxygen consumption
  • Thiol

ASJC Scopus subject areas

  • General

Cite this

Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis. / Vilchèze, Catherine; Hartman, Travis; Weinrick, Brian; Jain, Paras; Weisbrod, Torin R.; Leung, Lawrence W.; Freundlich, Joel S.; Jacobs, William R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 17, 25.04.2017, p. 4495-4500.

Research output: Contribution to journalArticle

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