An Antibacterial β‐Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis |
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| Authors: | Dr. Johannes Lehmann Dr. Tan‐Yun Cheng Dr. Anup Aggarwal Dr. Annie S. Park Dr. Evelyn Zeiler Dr. Ravikiran M. Raju Dr. Tatos Akopian Dr. Olga Kandror Prof. Dr. James C. Sacchettini Prof. Dr. D. Branch Moody Prof. Dr. Eric J. Rubin Prof. Dr. Stephan A. Sieber |
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| Affiliation: | 1. Center for Integrated Protein Science Department of Chemistry, Technische Universit?t München, Garching, Germany;2. Division of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA;3. Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA;4. Department of Biochemistry and Biophysics, Texas A&M University, TX, USA |
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| Abstract: | 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 β‐lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β‐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 13C metabolite profiling showed that both targets are functionally impaired by the β‐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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| Keywords: | activity-based protein profiling antibacterial compounds antibiotics Mycobacterium tuberculosis proteomics |
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