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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1302114110

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

Publication TypeJournal Article
Year of Publication2013
AuthorsStanley, SA, Kawate, T, Iwase, N, Shimizu, M, Clatworthy, AE, Kazyanskaya, E, Sacchettini, JC, Ioerger, TR, Siddiqi, NA, Minami, S, Aquadro, JA, Grant, SSchmidt, Rubin, EJ, Hung, DT
JournalProc Natl Acad Sci U S A
Date Published2013 Jul 09
KeywordsAnimals, Bacterial Proteins, Coumarins, Mice, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Mycolic Acids, Zebrafish

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23798446
PubMed Central IDPMC3710825
Grant ListK08 AI085033 / AI / NIAID NIH HHS / United States
U54 AI057159 / AI / NIAID NIH HHS / United States
AI057159 / AI / NIAID NIH HHS / United States