Resistance to thiacetazone derivatives active against Mycobacterium abscessus involves mutations in the MmpL5 transcriptional repressor MAB_4384

Halloum, Iman and Viljoen, Albertus and Khanna, Varun and Craig, Derek and Bouchier, Christiane and Brosch, Roland and Coxon, Geoffrey and Kremer, Laurent (2017) Resistance to thiacetazone derivatives active against Mycobacterium abscessus involves mutations in the MmpL5 transcriptional repressor MAB_4384. Antimicrobial Agents and Chemotherapy, 61 (4). e02509-16:1-14. e02509-16. ISSN 0066-4804 (https://doi.org/10.1128/AAC.02509-16)

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Abstract

Available chemotherapeutic options are very limited against Mycobacterium abscessus, which imparts a particular challenge in the treatment of cystic fibrosis (CF) patients infected with this rapid-growing mycobacterium. New drugs are urgently needed against this emerging pathogen, but the discovery of active chemotypes has not been performed intensively. Interestingly, however, the repurposing of thiacetazone (TAC), a drug once used to treat tuberculosis, has increased following the deciphering of its mechanism of action and the detection of significantly more potent analogues. We, therefore, report studies performed on a library of 38 TAC-related derivatives, previously evaluated for their antitubercular activity. Several compounds, including D6, D15 and D17, were found to exhibit potent activity in vitro against M. abscessus, Mycobacterium massiliense and Mycobacterium bolletii clinical isolates from CF and non-CF patients. Similarly to TAC in M. tuberculosis, the three analogues act as pro-drugs in M. abscessus, requiring bioactivation by the EthA enzyme, MAB_0985. Importantly, mutations in the transcriptional TetR repressor MAB_4384, with concomitant upregulation of the divergently oriented adjacent genes encoding an MmpS5/MmpL5 efflux pump system, accounted for high cross-resistance levels among all three compounds. Overall, this study uncovered a new mechanism of drug resistance in M. abscessus and demonstrated that simple structural optimization of the TAC scaffold can lead to the development of new drug candidates against M. abscessus infections.

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