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Cell. 2017 Jul 13;170(2):249-259.e25. doi: 10.1016/j.cell.2017.06.025. Epub 2017 Jun 29.

Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13.

Author information

1
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
2
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
3
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Department of Immunology and Infectious Disease, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
5
Structure-guided Drug Discovery Coalition, SGC Toronto, ON, Canada.
6
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
7
Department of Computer Science and Engineering, Texas A&M University, College Station, TX, USA.
8
NRF Centre of Excellence for Biomedical TB Research and the South African MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa.
9
Institute of Medical Microbiology, National Center for Mycobacteria, University of Zurich, Zurich, Switzerland.
10
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA. Electronic address: sacchett@tamu.edu.

Abstract

Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.

KEYWORDS:

Mycobacterium tuberculosis; Pks13 thioesterase domain; benzofuran inhibitors; crystal structure; polyketide synthase; structure-based drug discovery

PMID:
28669536
PMCID:
PMC5509550
DOI:
10.1016/j.cell.2017.06.025
[Indexed for MEDLINE]
Free PMC Article

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