Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13 | Academic Article individual record
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.

author list (cited authors)
Aggarwal, A., Parai, M. K., Shetty, N., Wallis, D., Woolhiser, L., Hastings, C., ... Sacchettini, J. C.
publication date
2017
publisher
Elsevier bv Publisher
published in
CELL Journal
keywords
  • Mice, Inbred BALB C
  • Female
  • Polyketide Synthase
  • Benzofurans
  • Drug Design
  • Specific Pathogen-Free Organisms
  • Tuberculosis
  • Structure-based Drug Discovery
  • Drug Resistance, Bacterial
  • Mice
  • Benzofuran Inhibitors
  • Models, Molecular
  • Mycobacterium Tuberculosis
  • Crystal Structure
  • Cell Line
  • Animals
  • Pks13 Thioesterase Domain
  • Antitubercular Agents
  • Piperidines