An Antibacterial ß-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis.
Angew Chem Int Ed Engl
; 57(1): 348-353, 2018 01 02.
Article
em En
| MEDLINE
| ID: mdl-29067779
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 ß-lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of ß-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 13 C metabolite profiling showed that both targets are functionally impaired by the ß-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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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lactonas
/
Mycobacterium tuberculosis
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Ácidos Micólicos
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Antituberculosos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article