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

doi:10.1007/s12275-013-3099-4

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Detection of Inhibitors of Phenotypically Drug-tolerant Mycobacterium tuberculosis Using an In Vitro Bactericidal Screen: Ian M. Bassett ¹, Shichun Lun ², William R. Bishai ², Haidan Guo ², Joanna R. Kirman ³, Mudassar Altaf ¹, Ronan F. O’Toole ⁴; Journal of Microbiology 2013;51(5):651-658.
DOI: https://doi.org/10.1007/s12275-013-3099-4
Published online: June 25, 2013

¹School of Biological Sciences, Victoria University of Wellington, New Zealand, ²Center for Tuberculosis Research, Johns Hopkins University, Baltimore, USA, ³Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand, ⁴Department of Clinical Microbiology, School of Medicine, Trinity College Dublin, Ireland¹School of Biological Sciences, Victoria University of Wellington, New Zealand, ²Center for Tuberculosis Research, Johns Hopkins University, Baltimore, USA, ³Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand, ⁴Department of Clinical Microbiology, School of Medicine, Trinity College Dublin, Ireland

Corresponding author: Ronan F. O’Toole , Tel: +353-1-896-4551,

Received: 13 February 2013 • Accepted: 24 April 2013

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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.

Keywords: Mycobacterium tuberculosis;phenotypic drug tolerance;chemical library screening

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Detection of Inhibitors of Phenotypically Drug-tolerant Mycobacterium tuberculosis Using an In Vitro Bactericidal Screen

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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