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Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4495-4500. doi: 10.1073/pnas.1704376114. Epub 2017 Apr 10.

Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis.

Author information

1
Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461.
2
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.
3
Gray Box Biology LLC, New York, NY 10027.
4
Department of Medicine, Center for Emerging and Reemerging Pathogens, New Jersey Medical School, Newark, NJ 07103.
5
Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461; jacobsw@hhmi.org.

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 concentration- and 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.

KEYWORDS:

drug resistance; mycobacterial persister; oxygen consumption; thiol

PMID:
28396391
PMCID:
PMC5410800
DOI:
10.1073/pnas.1704376114
[Indexed for MEDLINE]
Free PMC Article

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