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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 28; pp. 11565 - 11570
• Main Authors: Stanley, Sarah A., Kawate, Tomohiko, Iwase, Noriaki, Shimizu, Motohisa, Clatworthy, Anne E., Kazyanskaya, Edward, Sacchettini, James C., Ioerger, Thomas R., Siddiqi, Noman A., Minami, Shoko, Aquadro, John A., Grant, Sarah Schmidt, Rubin, Eric J., Hung, Deborah T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.07.2013; National Acad Sciences
• Subjects: Animals; Antibiotics; Antituberculars; Bacteria; Bacterial Proteins - drug effects; Bacterial Proteins - metabolism; Biological Sciences; Biosynthesis; Coumarins; Coumarins - pharmacology; Drug therapy; Embryos; Fatty acids; Infections; Mice; Microbial Sensitivity Tests; Molecules; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - metabolism; Mycolic acids; Mycolic Acids - metabolism; Proteins; Public health; Tuberculosis; Zebrafish
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1302114110

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.