Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13. Academic Article uri icon

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.

published proceedings

  • Cell

altmetric score

  • 61.11

author list (cited authors)

  • Aggarwal, A., Parai, M. K., Shetty, N., Wallis, D., Woolhiser, L., Hastings, C., ... Sacchettini, J. C

citation count

  • 85

complete list of authors

  • 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

publication date

  • June 2017

published in