Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28669536.
- Also identified by DOI 10.1016/j.cell.2017.06.025 and PMC identifier 5509550.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Antitubercular Agents
- Benzofurans
- Drug Design
- Drug Resistance, Bacterial
- Mycobacterium tuberculosis
- Piperidines
- Tuberculosis