期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 24, 页码 E4832-E4840出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705385114
关键词
Mycobacterium tuberculosis; differentially detectable; phenotypic tolerance; rifampin; thioridazine
资金
- Tri-Institutional TB Research Unit (NIH) [U19 AI111143-01]
- NIH [T32 AI007613, K08AI108799, TBRU U19 AI111276, R01 AI026170]
- Human Frontier Science Program Organization
- Milstein Program in Chemical Biology and Translational Medicine
- William Randolph Hearst Trust
Mycobacterium tuberculosis (Mtb) encounters stresses during the pathogenesis and treatment of tuberculosis (TB) that can suppress replication of the bacteria and render them phenotypically tolerant to most available drugs. Where studied, the majority of Mtb in the sputum of most untreated subjects with active TB have been found to be nonreplicating by the criterion that they do not grow as colony-forming units (cfus) when plated on agar. However, these cells are viable because they grow when diluted in liquid media. A method for generating such differentially detectable (DD) Mtb in vitro would aid studies of the biology and drug susceptibility of this population, but lack of independent confirmation of reported methods has contributed to skepticism about their existence. Here, we identified confounding artifacts that, when avoided, allowed development of a reliable method of producing cultures of >= 90% DD Mtb in starved cells. We then characterized several drugs according to whether they contribute to the generation of DD Mtb or kill them. Of the agents tested, rifamycins led to DD Mtb generation, an effect lacking in a rifampin-resistant strain with a mutation in rpoB, which encodes the canonical rifampin target, the beta subunit of RNA polymerase. In contrast, thioridazine did not generate DD Mtb from starved cells but killed those generated by rifampin.
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