An Antibacterial β‐Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis | Academic Article individual record
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 13 C 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.

author list (cited authors)
Lehmann, J., Cheng, T., Aggarwal, A., Park, A. S., Zeiler, E., Raju, R. M., ... Sieber, S. A.
publication date
2018
publisher
Wiley Publisher
keywords
  • Antibacterial Compounds
  • Activity-based Protein Profiling
  • Antibiotics
  • Mycobacterium Tuberculosis
  • Proteomics
altmetric score

132.33

citation count

13

PubMed Central ID
29067779
identifier
292538SE
Digital Object Identifier (DOI)
start page
348
end page
353
volume
57
issue
1