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An antibacterial β-lactone kills Mycobacterium tuberculosis by infiltrating mycolic acid biosynthesis

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap XL

ORGANISM(S): Mycobacterium Smegmatis (strain Atcc 700084 / Mc(2)155) Mycobacterium Tuberculosis H37rv

DISEASE(S): Tuberculosis

SUBMITTER: Nina Bach

LAB HEAD: Prof. Stephan A. Sieber

PROVIDER: PXD007699 | Pride | 2022-01-19

REPOSITORIES: Pride

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An Antibacterial β-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis.

Lehmann Johannes J Cheng Tan-Yun TY Aggarwal Anup A Park Annie S AS Zeiler Evelyn E Raju Ravikiran M RM Akopian Tatos T Kandror Olga O Sacchettini James C JC Moody D Branch DB Rubin Eric J EJ Sieber Stephan A SA

Angewandte Chemie (International ed. in English) 20171205 1

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 ...[more]

PMID: 29067779

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