Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32.

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

Infection with the bacterial pathogen Mycobacterium tuberculosis imposes an enormous burden on global public health. New antibiotics are urgently needed to combat the global tuberculosis pandemic; however, the development of new small molecules is hindered by a lack of validated drug targets. Here, we describe the identification of a 4,6-diaryl-5,7-dimethyl coumarin series that kills M. tuberculosis by inhibiting fatty acid degradation protein D32 (FadD32), an enzyme that is required for biosynthesis of cell-wall mycolic acids. These substituted coumarin inhibitors directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32. They effectively block bacterial replication both in vitro and in animal models of tuberculosis, validating FadD32 as a target for antibiotic development that works in the same pathway as the established antibiotic isoniazid. Targeting new steps in well-validated biosynthetic pathways in antitubercular therapy is a powerful strategy that removes much of the usual uncertainty surrounding new targets and in vivo clinical efficacy, while circumventing existing resistance to established targets.

Year of Publication
2013
Journal
Proc Natl Acad Sci U S A
Volume
110
Issue
28
Pages
11565-70
Date Published
2013 Jul 09
ISSN
1091-6490
URL
DOI
10.1073/pnas.1302114110
PubMed ID
23798446
PubMed Central ID
PMC3710825
Links
Grant list
K08 AI085033 / AI / NIAID NIH HHS / United States
U54 AI057159 / AI / NIAID NIH HHS / United States
AI057159 / AI / NIAID NIH HHS / United States