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Title: EthA/R-Independent Killing of Mycobacterium tuberculosis by Ethionamide
Authors: Ang, Michelle L. T.
Zainul Rahim, Siti Z.
de Sessions, Paola Florez
Lin, Wenwei
Koh, Vanessa
Pethe, Kevin
Hibberd, Martin L.
Alonso, Sylvie
Keywords: Ethionamide
Mycobacterium tuberculosis
Issue Date: 2017
Source: Ang, M. L. T., Zainul Rahim, S. Z., de Sessions, P. F., Lin, W., Koh, V., Pethe, K., et al. (2017). EthA/R-Independent Killing of Mycobacterium tuberculosis by Ethionamide. Frontiers in Microbiology, 8, 710-.
Series/Report no.: Frontiers in Microbiology
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 EthRindependent, 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.
DOI: 10.3389/fmicb.2017.00710
Schools: School of Biological Sciences 
Lee Kong Chian School of Medicine (LKCMedicine) 
Rights: © 2017 Ang, Zainul Rahim, de Sessions, Lin, Koh, Pethe, Hibberd and Alonso. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
SBS Journal Articles

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