期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 57, 期 1, 页码 348-353出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201709365
关键词
activity-based protein profiling; antibacterial compounds; antibiotics; Mycobacterium tuberculosis; proteomics
资金
- Deutsche Forschungsgemeinschaft [SFB749]
- Studienstiftung des deutschen Volkes
- National Institute of Health [AI U19 111224]
The spread of antibiotic resistance is a major challenge for the treatment of Mycobacterium tuberculosis infections. In addition, the efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis, leading to rapid cell death. Inspired by this mechanism, we exploited -lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of -lactones, we found one hit with potent anti-mycobacterial and bactericidal activity. Chemical proteomics using an alkynylated probe identified Pks13 and Ag85 serine hydrolases as major targets. Validation through enzyme assays and customized C-13 metabolite profiling showed that both targets are functionally impaired by the beta-lactone. Co-administration with front-line antibiotics enhanced the potency against M. tuberculosis by more than 100-fold, thus demonstrating the therapeutic potential of targeting mycomembrane biosynthesis serine hydrolases.
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