An antibacterial β-lactone kills Mycobacterium tuberculosis by infiltrating mycolic acid biosynthesis
| Autor: | Evelyn Zeiler, Anup Aggarwal, James C. Sacchettini, Stephan A. Sieber, Eric J. Rubin, Ravikiran M. Raju, Olga Kandror, Tan-Yun Cheng, Tatos Akopian, Johannes Lehmann, D. Branch Moody, Annie S. Park |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Tuberculosis Cell Membrane Permeability medicine.drug_class Antibiotics Antitubercular Agents Microbial Sensitivity Tests Catalysis Article Mycolic acid Mycobacterium tuberculosis Serine 03 medical and health sciences chemistry.chemical_compound Lactones Antibiotic resistance Biosynthesis Bacterial Proteins medicine chemistry.chemical_classification Antigens Bacterial biology Activity-based proteomics General Chemistry medicine.disease biology.organism_classification 030104 developmental biology chemistry Biochemistry Mycolic Acids Polyketide Synthases Acyltransferases |
| Popis: | The spread of antibiotic resistance is a major challenge for treatment of Mycobacterium tuberculosis infection. In addition, 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 exploit 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 via 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 demonstrating a therapeutic potential of targeting mycomembrane biosynthesis serine hydrolases. |
| Databáze: | OpenAIRE |
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