Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. Academic Article uri icon

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.

published proceedings

  • Proc Natl Acad Sci U S A

altmetric score

  • 0.25

author list (cited authors)

  • Stanley, S. A., Kawate, T., Iwase, N., Shimizu, M., Clatworthy, A. E., Kazyanskaya, E., ... Hung, D. T

citation count

  • 71

complete list of 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

publication date

  • June 2013