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dc.contributor.authorStanley, Sarah
dc.contributor.authorKawate, Tomohiko
dc.contributor.authorIwase, Noriaki
dc.contributor.authorShimizu, Motohisa
dc.contributor.authorClatworthy, Anne
dc.contributor.authorKazyanskaya, Edward
dc.contributor.authorSacchettini, James
dc.contributor.authorIoerger, Thomas
dc.contributor.authorSiddiqi, Noman
dc.contributor.authorMinami, Shoko
dc.contributor.authorAquadro, John
dc.contributor.authorGrant, Sarah Schmidt
dc.contributor.authorRubin, Eric
dc.contributor.authorHung, Deborah
dc.date.accessioned2019-10-13T16:02:42Z
dc.date.issued2013
dc.identifier.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.
dc.identifier.issn0027-8424
dc.identifier.issn0744-2831
dc.identifier.issn1091-6490
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41542751*
dc.description.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.
dc.language.isoen_US
dc.publisherNational Academy of Sciences
dash.licenseLAA
dc.titleDiarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalProceedings of the National Academy of Sciences of the United States of America
dash.depositing.authorHung, Deborah Tan::45968263d9ae67f8c1970987265073e7::600
dc.date.available2019-10-13T16:02:42Z
dash.workflow.comments1Science Serial ID 90998
dc.identifier.doi10.1073/pnas.1302114110
dash.source.volume110;28
dash.source.page11565


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