Detection of inhibitors of phenotypically drug-tolerant Mycobacterium tuberculosis using an in vitro bactericidal screen

Ian M. Bassett, Shichun Lun, William R. Bishai, Haidan Guo, Joanna R. Kirman, Mudassar Altaf, Ronan F. O'Toole

Research output: Contribution to journalArticlepeer-review

Abstract

Many whole cell screens of chemical libraries currently in use are based on inhibition of bacterial growth. The goal of this study was to develop a chemical library screening model that enabled detection of compounds that are active against drug-tolerant non-growing cultures of Mycobacterium tuberculosis. An in vitro model of low metabolically active mycobacteria was established with 8 and 30 day old cultures of M. smegmatis and M. tuberculosis, respectively. Reduction of resazurin was used as a measure of viability and the assay was applied in screens of chemical libraries for bactericidal compounds. The model provided cells that were phenotypically-resilient to killing by first and second-line clinical drugs including rifampicin. Screening against chemical libraries identified proteasome inhibitors, NSC310551 and NSC321206, and a structurally-related series of thiosemicarbazones, as having potent killing activity towards aged cultures. The inhibitors were confirmed as active against virulent M. tuberculosis strains including multi- and extensively-drug resistant clinical isolates. Our library screen enabled detection of compounds with a potent level of bactericidal activity towards phenotypically drug-tolerant cultures of M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)651-658
Number of pages8
JournalJournal of Microbiology
Volume51
Issue number5
DOIs
StatePublished - Oct 1 2013

Keywords

  • Mycobacterium tuberculosis
  • chemical library screening
  • phenotypic drug tolerance

ASJC Scopus subject areas

  • Microbiology
  • Applied Microbiology and Biotechnology

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