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Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations.

TitleRifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations.
Publication TypeJournal Article
Year of Publication2017
AuthorsSaito K, Warrier T, Somersan-Karakaya S, Kaminski L, Mi J, Jiang X, Park S, Shigyo K, Gold B, Roberts J, Weber E, Jacobs WR, Nathan C
JournalProc Natl Acad Sci U S A
Volume114
Issue24
PaginationE4832-E4840
Date Published2017 Jun 13
ISSN1091-6490
Abstract

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 β subunit of RNA polymerase. In contrast, thioridazine did not generate DD Mtb from starved cells but killed those generated by rifampin.

DOI10.1073/pnas.1705385114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28559332
PubMed Central IDPMC5474769
Grant ListU19 AI111143 / AI / NIAID NIH HHS / United States
K08 AI108799 / AI / NIAID NIH HHS / United States
U19 AI111276 / AI / NIAID NIH HHS / United States
T32 AI007613 / AI / NIAID NIH HHS / United States
R01 AI026170 / AI / NIAID NIH HHS / United States