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

Anup Aggarwal, Maloy K. Parai, Nishant Shetty, Deeann Wallis, Lisa Woolhiser, Courtney Hastings, Noton K. Dutta, Stacy Galaviz, Ramesh C. Dhakal, Rupesh Shrestha, Shoko Wakabayashi, Chris Walpole, David Matthews, David Floyd, Paul Scullion, Jennifer Riley, Ola Epemolu, Suzanne Norval, Thomas Snavely, Gregory T. RobertsonEric J. Rubin, Thomas R. Ioerger, Frik A. Sirgel, Ruben van der Merwe, Paul D. van Helden, Peter A. Keller, Erik C. Böttger, Petros C. Karakousis, Anne J. Lenaerts, James C. Sacchettini

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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. A small molecule inhibitor of M. tuberculosis polyketide synthase shows strong efficacy in murine models of infection.

Original languageEnglish
Pages (from-to)249-259.e25
Number of pages36
JournalCell
Volume170
Issue number2
Early online date29 Jun 2017
DOIs
Publication statusPublished - 13 Jul 2017

Keywords

  • Benzofuran inhibitors
  • Crystal structure
  • Mycobacterium tuberculosis
  • Pks13 thioesterase domain
  • Polyketide synthase
  • Structure-based drug discovery

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