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


Bassett, IM and Lun, S and Bishai, WR and Guo, H and Kirman, JR and Altaf, M and O'Toole, RF, Detection of inhibitors of phenotypically drug-tolerant Mycobacterium tuberculosis using an in vitro bactericidal screen, Journal of Microbiology, 51, (5) pp. 651-658. ISSN 1225-8873 (2013) [Refereed Article]

DOI: doi:10.1007/s12275-013-3099-4


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.

Item Details

Item Type:Refereed Article
Keywords:chemical library screening; Mycobacterium tuberculosis; phenotypic drug tolerance
Research Division:Biomedical and Clinical Sciences
Research Group:Medical microbiology
Research Field:Medical bacteriology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:O'Toole, RF (Dr Ronan O'Toole)
ID Code:95689
Year Published:2013
Web of Science® Times Cited:8
Deposited By:Medicine
Deposited On:2014-10-07
Last Modified:2017-11-07

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