title: Resistance to Thiacetazone Derivatives Active against Mycobacterium abscessus Involves Mutations in the MmpL5 Transcriptional Repressor MAB_4384.
abstract: Available chemotherapeutic options are very limited againstMycobacterium abscessus, which imparts a particular challenge in the treatment of cystic fibrosis (CF) patients infected with this rapidly 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 activityin vitroagainstM. abscessus,Mycobacterium massiliense, andMycobacterium bolletiiclinical isolates from CF and non-CF patients. Similar to TAC inMycobacterium tuberculosis, the three analogues act as prodrugs inM. 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 inM. abscessusand demonstrated that simple structural optimization of the TAC scaffold can lead to the development of new drug candidates againstM. abscessusinfections.
authors.affiliation: Centre National de la Recherche Scientifique FRE 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université de Montpellier, Montpellier France.
authors.forename: Iman
authors.initials: I
authors.lastname: Halloum
authors.affiliation: Centre National de la Recherche Scientifique FRE 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université de Montpellier, Montpellier France.
authors.forename: Albertus
authors.initials: A
authors.lastname: Viljoen
authors.affiliation: Institut Pasteur, Hub Bioinformatique et Biostatistique, C3BI, Unité de Services et de Recherche, USR 3756, Institut Pasteur CNRS, Paris, France.
authors.forename: Varun
authors.initials: V
authors.lastname: Khanna
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
authors.forename: Derek
authors.initials: D
authors.lastname: Craig
authors.affiliation: Institut Pasteur, PF1 Genopole, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Bouchier
authors.affiliation: Institut Pasteur, Unité de Pathogénomique Mycobactérienne Intégrée, Paris, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Coxon
authors.affiliation: Centre National de la Recherche Scientifique FRE 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université de Montpellier, Montpellier France laurent.kremer@cpbs.cnrs.fr.|INSERM, CPBS, Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D009161:Mycobacterium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013828:Thioacetazone / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D013828:Thioacetazone
keywords: MmpL; Mycobacterium abscessus; TetR regulator; drug resistance mechanism; therapeutic activity; thiacetazone