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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Jul 4

PMID 28669536

Citations 52

Authors

Anup Aggarwal

Maloy K Parai

Nishant Shetty

Deeann Wallis

Lisa Woolhiser

Courtney Hastings

Noton K Dutta

Stacy Galaviz

Ramesh C Dhakal

Rupesh Shrestha

Shoko Wakabayashi

Chris Walpole

David Matthews

David Floyd

Paul Scullion

Jennifer Riley

Ola Epemolu

Suzanne Norval

Thomas Snavely

Gregory T Robertson

Eric J Rubin

Thomas R Ioerger

Frik A Sirgel

Ruben van der Merwe

Paul D van Helden

Peter Keller

Erik C Bottger

Petros C Karakousis

Anne J Lenaerts

James C Sacchettini

Affiliations

Soon will be listed here.

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.

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