Structure Report for: 5V3Z

Aggarwal, A., Sacchettini, J.C. (5F4F withdrawn)

Title: Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13
Aggarwal A, Parai MK, Shetty N, Wallis D, Woolhiser L, Hastings C, Dutta NK, Galaviz S, Dhakal RC and Sacchettini JC <20 more author(s)> Aggarwal A, Parai MK, Shetty N, Wallis D, Woolhiser L, Hastings C, Dutta NK, Galaviz S, Dhakal RC, Shrestha R, Wakabayashi S, Walpole C, Matthews D, Floyd D, Scullion P, Riley J, Epemolu O, Norval S, Snavely T, Robertson GT, Rubin EJ, Ioerger TR, Sirgel FA, van der Merwe R, van Helden PD, Keller P, Bottger EC, Karakousis PC, Lenaerts AJ, Sacchettini JC (- 20)
Ref: Cell, 170:249, 2017 : PubMed
Abstract


ESTHER: Aggarwal_2017_Cell_170_249
PubMedSearch: Aggarwal 2017 Cell 170 249
PubMedID: 28669536
Gene_locus related to this paper: myctu-PKS13
Inhibitor(s) related to this paper: 2Q5, TAM1, TAM16, TAM6, TAM5, Polypropyleneglycol-fragment-C8, TAM3

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 approximately 100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.