Rifamycin action on RNA polymerase in antibiotictolerant Mycobacterium tuberculosis results in differentially detectable populations Academic Article uri icon

Overview

MeSH Major

  • Adenosine Triphosphate
  • Gene Expression Regulation, Bacterial
  • Macrophages
  • Mycobacterium tuberculosis
  • Nitrates
  • Nitrites
  • Oxygen

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.

publication date

  • June 13, 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5474769

Digital Object Identifier (DOI)

  • 10.1073/pnas.1705385114

PubMed ID

  • 28559332

Additional Document Info

start page

  • E4832

end page

  • E4840

volume

  • 114

number

  • 24