| Literature DB >> 28669536 |
Anup Aggarwal1, Maloy K Parai1, Nishant Shetty1, Deeann Wallis1, Lisa Woolhiser2, Courtney Hastings2, Noton K Dutta3, Stacy Galaviz1, Ramesh C Dhakal1, Rupesh Shrestha1, Shoko Wakabayashi4, Chris Walpole5, David Matthews5, David Floyd5, Paul Scullion6, Jennifer Riley6, Ola Epemolu6, Suzanne Norval6, Thomas Snavely1, Gregory T Robertson2, Eric J Rubin4, Thomas R Ioerger7, Frik A Sirgel8, Ruben van der Merwe8, Paul D van Helden8, Peter Keller9, Erik C Böttger9, Petros C Karakousis3, Anne J Lenaerts2, James C Sacchettini10.
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.Entities:
Keywords: Mycobacterium tuberculosis; Pks13 thioesterase domain; benzofuran inhibitors; crystal structure; polyketide synthase; structure-based drug discovery
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Year: 2017 PMID： 28669536 PMCID： PMC5509550 DOI： 10.1016/j.cell.2017.06.025
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582