AI Article Synopsis
- Widespread resistance to first-line TB drugs necessitates developing new treatments, focusing on novel mechanisms to combat the bacteria.
- Researchers have created a lead molecule called TAM16, which effectively targets polyketide synthase Pks13, an enzyme crucial for Mycobacterium tuberculosis's cell wall.
- TAM16 demonstrates strong bactericidal activity and comparable efficacy to the main TB drug isoniazid in animal models, with a much lower chance of developing resistance, making it a promising candidate for new TB therapies.
Article 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.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509550 | PMC |
| http://dx.doi.org/10.1016/j.cell.2017.06.025 | DOI Listing |
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