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KMID : 0880220130510050651
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Journal of Microbiology
2013 Volume.51 No. 5 p.651 ~ p.658
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Detection of Inhibitors of Phenotypically Drug-tolerant Mycobacterium tuberculosis Using an In Vitro Bactericidal Screen
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Ian M. Bassett
Mudassar Altaf
Shichun Lun
William R. Bishai
Haidan Guo
Joanna R. Kirman
Ronan F. O’Toole
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Abstract
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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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KEYWORD
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Mycobacterium tuberculosis, phenotypic drug tolerance, chemical library screening
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