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Title: EthA/R-independent killing of Mycobacterium tuberculosis by ethionamide
Authors: Ang, M.L.T 
Rahim, S.Z.Z 
de Sessions P.F
Lin, W 
Koh, V 
Hibberd, M.L 
Alonso, S 
Keywords: ethionamide
bacterial strain
bacterium isolation
bovine tuberculosis
drug sensitivity
Escherichia coli
gene mutation
growth inhibition
multidrug resistant tuberculosis
Mycobacterium tuberculosis
next generation sequencing
single nucleotide polymorphism
Southern blotting
spontaneous mutation
whole genome sequencing
Issue Date: 2017
Citation: Ang, M.L.T, Rahim, S.Z.Z, de Sessions P.F, Lin, W, Koh, V, Pethe.K, Hibberd, M.L, Alonso, S (2017). EthA/R-independent killing of Mycobacterium tuberculosis by ethionamide. Frontiers in Microbiology 8 (APR) : 710. ScholarBank@NUS Repository.
Abstract: Ethionamide (ETH) is part of the drug arsenal available to treat multi-drug resistant tuberculosis. The current paradigm of this pro-drug activation involves the mycobacterial enzyme EthA and the transcriptional repressor, EthR. However, several lines of evidence suggest the involvement of additional players. The ethA/R locus was deleted in Mycobacterium bovis BCG and three Mycobacterium tuberculosis (MTB) strains. While complete resistance to ETH was observed with BCG ethA/R KO, drug susceptibility and dose-dependent killing were retained in the ethA/R KO MTB mutants, suggesting the existence of an alternative pathway of ETH bio-activation in MTB. We further demonstrated that this alternative pathway is EthR-independent, whereby re-introduction of ethR in ethA/R KO MTB did not lead to increased resistance to ETH. Consistently, ethA KO MTB (with intact ethR expression) displayed similar ETH susceptibility profile as their ethA/R KO counterparts. To identify the alternative ETH bio-activator, spontaneous ETH-resistant mutants were obtained from ethA/R KO MTB and whole genome sequencing identified single nucleotide polymorphisms in mshA, involved in mycothiol biosynthesis and previously linked to ETH resistance. Deletion of mshA in ethA/R KO MTB led to complete ETH resistance, supporting that the role of MshA in ETH killing is EthA/R-independent. Furthermore mshA single KO MTB displayed levels of ETH resistance similar or greater than those obtained with ethA/R KO strains, supporting that mshA is as critical as ethA/R for ETH killing efficacy. © 2017 Ang, Zainul Rahim, de Sessions, Lin, Koh, Pethe, Hibberd and Alonso.
Source Title: Frontiers in Microbiology
ISSN: 1664302X
DOI: 10.3389/fmicb.2017.00710
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