Journal of Microbiology

Research Support, Non-U.S. Gov't

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; J. Microbiol. 2013;51(5):651-658. Published online June 25, 2013; DOI: https://doi.org/10.1007/s12275-013-3099-4

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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.

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