Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32
Grant, Sarah Schmidt
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CitationStanley, 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.
AbstractInfection 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.
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