2. Academic Validation
  3. Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis

Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis

  • J Med Chem. 2018 Feb 8;61(3):791-803. doi: 10.1021/acs.jmedchem.7b01319.
Wei Zhang,  Shichun Lun 1,  Shu-Huan Wang,  Xing-Wu Jiang 2,  Fan Yang,  Jie Tang,  Abigail L Manson 3,  Ashlee M Earl 3,  Hendra Gunosewoyo 4,  William R Bishai 1,  Li-Fang Yu
Affiliations

Affiliations

  • 1 Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine , Baltimore, Maryland 21231-1044, United States.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, and School of Life Sciences, East China Normal University , 500 Dongchuan Road, Shanghai 200241, China.
  • 3 Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
  • 4 School of Pharmacy, Faculty of Health Sciences, Curtin University , Bentley, Perth, Western Australia 6102, Australia.
PMID: 29328655 DOI: 10.1021/acs.jmedchem.7b01319
Abstract

Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.

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