Dataset Information

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

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.

SUBMITTER: Aggarwal A

PROVIDER: S-EPMC5509550 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Aggarwal Anup A Parai Maloy K MK Shetty Nishant N Wallis Deeann D Woolhiser Lisa L Hastings Courtney C Dutta Noton K NK Galaviz Stacy S Dhakal Ramesh C RC Shrestha Rupesh R Wakabayashi Shoko S Walpole Chris C Matthews David D Floyd David D Scullion Paul P Riley Jennifer J Epemolu Ola O Norval Suzanne S Snavely Thomas T Robertson Gregory T GT Rubin Eric J EJ Ioerger Thomas R TR Sirgel Frik A FA van der Merwe Ruben R van Helden Paul D PD Keller Peter P Böttger Erik C EC Karakousis Petros C PC Lenaerts Anne J AJ Sacchettini James C JC

Cell 20170629 2

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 bacteric ...[more]

PMID: 28669536

Similar Datasets

Project description:BackgroundType I polyketide synthases (PKSs) are multifunctional enzymes responsible for the biosynthesis of a group of diverse natural compounds with biotechnological and pharmaceutical interest called polyketides. The diversity of polyketides is impressive despite the limited set of catalytic domains used by PKSs for biosynthesis, leading to considerable interest in deciphering their structure-function relationships, which is challenging due to high intrinsic flexibility. Among nineteen polyketide synthases encoded by the genome of Mycobacterium tuberculosis, Pks13 is the condensase required for the final condensation step of two long acyl chains in the biosynthetic pathway of mycolic acids, essential components of the cell envelope of Corynebacterineae species. It has been validated as a promising druggable target and knowledge of its structure is essential to speed up drug discovery to fight against tuberculosis.ResultsWe report here a quasi-atomic model of Pks13 obtained using small-angle X-ray scattering of the entire protein and various molecular subspecies combined with known high-resolution structures of Pks13 domains or structural homologues. As a comparison, the low-resolution structures of two other mycobacterial polyketide synthases, Mas and PpsA from Mycobacterium bovis BCG, are also presented. This study highlights a monomeric and elongated state of the enzyme with the apo- and holo-forms being identical at the resolution probed. Catalytic domains are segregated into two parts, which correspond to the condensation reaction per se and to the release of the product, a pivot for the enzyme flexibility being at the interface. The two acyl carrier protein domains are found at opposite sides of the ketosynthase domain and display distinct characteristics in terms of flexibility.ConclusionsThe Pks13 model reported here provides the first structural information on the molecular mechanism of this complex enzyme and opens up new perspectives to develop inhibitors that target the interactions with its enzymatic partners or between catalytic domains within Pks13 itself.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets