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02 2018 The Journal of biological chemistry

Cyclipostins and cyclophostin analogs inhibit the antigen 85C from both and .

Auteurs

Viljoen A, Richard M, Fourquet P, Camoin L, Paudal RR, Gnawali GR, Spilling CD, Cavalier JF, Canaan S, Kremer L

Résumé

An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of cyclipostins and cyclophostin (CyC) analogs exhibiting potent activity against both and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds. These targets included members of the antigen 85 (Ag85) complex ( Ag85A, Ag85B, and Ag85C), responsible for biosynthesis of trehalose dimycolate and mycolylation of arabinogalactan. Herein, we used biochemical and structural approaches to validate the Ag85 complex as a pharmacological target of the CyC analogs. We found that CyC, CyC, and CyC bind covalently to the catalytic Ser residue in Ag85C; inhibit mycolyltransferase activity ( the transfer of a fatty acid molecule onto trehalose); and reduce triacylglycerol synthase activity, a property previously attributed to Ag85A. Supporting these results, an X-ray structure of Ag85C in complex with CyC disclosed that this inhibitor occupies Ag85C’s substrate-binding pocket. Importantly, metabolic labeling of cultures revealed that the CyC compounds impair both trehalose dimycolate synthesis and mycolylation of arabinogalactan. Overall, our study provides compelling evidence that CyC analogs can inhibit the activity of the Ag85 complex and in mycobacteria, opening the door to a new strategy for inhibiting Ag85. The high-resolution crystal structure obtained will further guide the rational optimization of new CyC scaffolds with greater specificity and potency against .

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