dc.contributor.author | Stanley, Sarah | |
dc.contributor.author | Kawate, Tomohiko | |
dc.contributor.author | Iwase, Noriaki | |
dc.contributor.author | Shimizu, Motohisa | |
dc.contributor.author | Clatworthy, Anne | |
dc.contributor.author | Kazyanskaya, Edward | |
dc.contributor.author | Sacchettini, James | |
dc.contributor.author | Ioerger, Thomas | |
dc.contributor.author | Siddiqi, Noman | |
dc.contributor.author | Minami, Shoko | |
dc.contributor.author | Aquadro, John | |
dc.contributor.author | Grant, Sarah Schmidt | |
dc.contributor.author | Rubin, Eric | |
dc.contributor.author | Hung, Deborah | |
dc.date.accessioned | 2019-10-13T16:02:42Z | |
dc.date.issued | 2013 | |
dc.identifier.citation | Stanley, 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. | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.issn | 0744-2831 | |
dc.identifier.issn | 1091-6490 | |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:41542751 | * |
dc.description.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. | |
dc.language.iso | en_US | |
dc.publisher | National Academy of Sciences | |
dash.license | LAA | |
dc.title | Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32 | |
dc.type | Journal Article | |
dc.description.version | Version of Record | |
dc.relation.journal | Proceedings of the National Academy of Sciences of the United States of America | |
dash.depositing.author | Hung, Deborah Tan::45968263d9ae67f8c1970987265073e7::600 | |
dc.date.available | 2019-10-13T16:02:42Z | |
dash.workflow.comments | 1Science Serial ID 90998 | |
dc.identifier.doi | 10.1073/pnas.1302114110 | |
dash.source.volume | 110;28 | |
dash.source.page | 11565 | |