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 locus was deleted in BCG and three (MTB) strains. While complete resistance to ETH was observed with BCG KO, drug susceptibility and dose-dependent killing were retained in the 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 in KO MTB did not lead to increased resistance to ETH. Consistently, KO MTB (with intact expression) displayed similar ETH susceptibility profile as their KO counterparts. To identify the alternative ETH bio-activator, spontaneous ETH-resistant mutants were obtained from KO MTB and whole genome sequencing identified single nucleotide polymorphisms in , involved in mycothiol biosynthesis and previously linked to ETH resistance. Deletion of in KO MTB led to complete ETH resistance, supporting that the role of MshA in ETH killing is EthA/R-independent. Furthermore single KO MTB displayed levels of ETH resistance similar or greater than those obtained with KO strains, supporting that is as critical as for ETH killing efficacy.
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| http://dx.doi.org/10.3389/fmicb.2017.00710 | DOI Listing |
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