dc.contributor.authorAng, Michelle L. T.
dc.contributor.authorZainul Rahim, Siti Z.
dc.contributor.authorde Sessions, Paola Florez
dc.contributor.authorLin, Wenwei
dc.contributor.authorKoh, Vanessa
dc.contributor.authorPethe, Kevin
dc.contributor.authorHibberd, Martin L.
dc.contributor.authorAlonso, Sylvie
dc.identifier.citationAng, 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-.en_US
dc.description.abstractEthionamide (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.en_US
dc.description.sponsorshipNMRC (Natl Medical Research Council, S’pore)en_US
dc.format.extent12 p.en_US
dc.relation.ispartofseriesFrontiers in Microbiologyen_US
dc.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.en_US
dc.subjectMycobacterium tuberculosisen_US
dc.titleEthA/R-Independent Killing of Mycobacterium tuberculosis by Ethionamideen_US
dc.typeJournal Article
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.description.versionPublished versionen_US

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