Scientific Publications

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

Publication TypeJournal Article
AuthorsStanley, SA, Kawate T., Iwase N., Shimizu M., Clatworthy AE, Kazyanskaya E., Sacchettini JC, Ioerger TR, Siddiqi NA, Minami S., Aquadro JA, Schmidt Grant S., Rubin EJ, and Hung DT
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.
Year of Publication2013
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue28
Pages11565-70
Date Published (YYYY/MM/DD)2013/07/09
ISSN Number0027-8424
DOI10.1073/pnas.1302114110
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/23798446?dopt=Abstract