Affiliation:
1. Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065
Abstract
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. tuberculosis
in 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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Cell Biology,Microbiology (medical),Genetics,General Immunology and Microbiology,Ecology,Physiology
Cited by
108 articles.
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