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

TY - JOUR

T1 - Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13

AU - Aggarwal, Anup

AU - Parai, Maloy K.

AU - Shetty, Nishant

AU - Wallis, Deeann

AU - Woolhiser, Lisa

AU - Hastings, Courtney

AU - Dutta, Noton K.

AU - Galaviz, Stacy

AU - Dhakal, Ramesh C.

AU - Shrestha, Rupesh

AU - Wakabayashi, Shoko

AU - Walpole, Chris

AU - Matthews, David

AU - Floyd, David

AU - Scullion, Paul

AU - Riley, Jennifer

AU - Epemolu, Ola

AU - Norval, Suzanne

AU - Snavely, Thomas

AU - Robertson, Gregory T.

AU - Rubin, Eric J.

AU - Ioerger, Thomas R.

AU - Sirgel, Frik A.

AU - van der Merwe, Ruben

AU - van Helden, Paul D.

AU - Keller, Peter A.

AU - Böttger, Erik C.

AU - Karakousis, Petros C.

AU - Lenaerts, Anne J.

AU - Sacchettini, James C.

N1 - This work was supported by grants from the Bill and Melinda Gates Foundation (OPP1024055), NIAID-NIH (TB Structural Genomics grant P01A1095208), Welch foundation (A-0015), and Structure-guided Drug Discovery Coalition (OPP1032548) to J.C.S.; the NIH/NIAID IDIQ Contract Task Order HHSN272201000009I/HHSN27200001 (Task A04) for the efficacy testing to A.J.L.

PY - 2017/7/13

Y1 - 2017/7/13

N2 - 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.

AB - 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.

KW - Benzofuran inhibitors

KW - Crystal structure

KW - Mycobacterium tuberculosis

KW - Pks13 thioesterase domain

KW - Polyketide synthase

KW - Structure-based drug discovery

UR - https://www.scopus.com/pages/publications/85021378117

U2 - 10.1016/j.cell.2017.06.025

DO - 10.1016/j.cell.2017.06.025

M3 - Article

C2 - 28669536

AN - SCOPUS:85021378117

SN - 0092-8674

VL - 170

SP - 249-259.e25

JO - Cell

JF - Cell

IS - 2

ER -