Stanley, SarahKawate, TomohikoIwase, NoriakiShimizu, MotohisaClatworthy, AnneKazyanskaya, EdwardSacchettini, JamesIoerger, ThomasSiddiqi, NomanMinami, ShokoAquadro, JohnGrant, Sarah SchmidtRubin, EricHung, Deborah2019-10-132013Stanley, S. A., T. Kawate, N. Iwase, M. Shimizu, A. E. Clatworthy, E. Kazyanskaya, J. C. Sacchettini, et al. 2013. “Diarylcoumarins Inhibit Mycolic Acid Biosynthesis and Kill Mycobacterium Tuberculosis by Targeting FadD32.” Proceedings of the National Academy of Sciences 110 (28): 11565–70. doi:10.1073/pnas.1302114110.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41542751Infection 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.en-USJournal Article2019-10-1310.1073/pnas.1302114110