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

Academic 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 [Figure presented]
  • Authors

    Published In

  • Cell  Journal
  • Digital Object Identifier (doi)

    Author List

  • Aggarwal A; Parai MK; Shetty N; Wallis D; Woolhiser L; Hastings C; Dutta NK; Galaviz S; Dhakal RC; Shrestha R
  • Start Page

  • 249
  • End Page

  • 259.e25
  • Volume

  • 170
  • Issue

  • 2