期刊
CELL
卷 170, 期 2, 页码 249-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.06.025
关键词
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资金
- Bill and Melinda Gates Foundation [OPP1024055]
- NIAID-NIH (TB Structural Genomics grant) [P01A1095208]
- Welch foundation [A-0015]
- Structure-guided Drug Discovery Coalition [OPP1032548]
- NIH/NIAID IDIQ [HHSN272201000009I/HHSN27200001]
- South African MRC
- University of Zurich
- NRF
- Bill and Melinda Gates Foundation [OPP1024055, OPP1032548] Funding Source: Bill and Melinda Gates Foundation
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 similar to 100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection.
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