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 - http://www.scopus.com/inward/record.url?scp=85021378117&partnerID=8YFLogxK
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 -
