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

Aggarwal, Anup; Parai, Maloy K; Shetty, Nishant; Wallis, Deeann; Woolhiser, Lisa; Hastings, Courtney; Dutta, Noton K; Galaviz, Stacy; Dhakal, Ramesh C; Shrestha, Rupesh; Wakabayashi, Shoko; Walpole, Chris; Matthews, David; Floyd, David; Scullion, Paul; Riley, Jennifer; Epemolu, Ola; Norval, Suzanne; Snavely, Thomas; Robertson, Gregory T; Rubin, Eric J; Ioerger, Thomas R; Sirgel, Frik A; van der Merwe, Ruben; van Helden, Paul D; Keller, Peter; Böttger, Erik C; Karakousis, Petros C; Lenaerts, Anne J; Sacchettini, James C.
Cell; 170(2): 249-259.e25, 2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28669536
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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