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01, 2017;5 (1):

Targeting Phenotypically Tolerant Mycobacterium tuberculosis.

Ben Gold, Carl Nathan
Author Information
  1. Ben Gold: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065.
  2. Carl Nathan: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065.
PMID: 28233509 DOI: 10.1128/microbiolspec.TBTB2-0031-2016

Abstract

While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in clinical settings. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of posttreatment relapse. Some promising drugs to treat tuberculosis, such as rifampin and bedaquiline, only kill nonreplicating M. tuberculosisin vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high-throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores.

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Grants

  1. U19 AI111143/NIAID NIH HHS

MeSH Term

Antitubercular Agents
Drug Evaluation, Preclinical
Drug Tolerance
High-Throughput Screening Assays
Microbial Viability
Mycobacterium tuberculosis

Chemicals

Antitubercular Agents
Journal Article Review Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 7

Word Cloud

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