2. Academic Validation
  3. Discovery and structure-activity relationships of a novel oxazolidinone class of bacterial type II topoisomerase inhibitors

Discovery and structure-activity relationships of a novel oxazolidinone class of bacterial type II topoisomerase inhibitors

  • Bioorg Med Chem Lett. 2022 Jun 1:65:128648. doi: 10.1016/j.bmcl.2022.128648.
Amanda Lyons 1,  James Kirkham 2,  Kevin Blades 2,  David Orr 2,  Elizabeth Dauncey 1,  Oliver Smith 2,  Emma Dick 1,  Rolf Walker 1,  Teresa Matthews 1,  Adam Bunt 2,  Jonathan Finlayson 1,  Ian Morrison 1,  Victoria J Savage 2,  Emmanuel Moyo 2,  Hayley S Butler 1,  Rebecca Newman 2,  Nicola Ooi 2,  Andrew Smith 1,  Cédric Charrier 1,  Andrew J Ratcliffe 1,  Neil R Stokes 1,  Stuart Best 1,  Anne-Marie Salisbury 1,  Mark Craighead 1,  Ian R Cooper 3
Affiliations

Affiliations

  • 1 Redx Anti-Infectives Ltd, Alderley Park, Cheshire SK10 4TG, UK.
  • 2 Infex Therapeutics Ltd, Mereside, Alderley Park, Macclesfield SK10 4TG,UK.
  • 3 Infex Therapeutics Ltd, Mereside, Alderley Park, Macclesfield SK10 4TG,UK. Electronic address: ian.cooper@infextx.com.
PMID: 35231579 DOI: 10.1016/j.bmcl.2022.128648
Abstract

There is an increasingly urgent and unmet medical need for novel Antibiotic drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. Novel Bacterial type II Topoisomerase inhibitors (NBTIs) are of high interest due to limited cross-resistance with fluoroquinolones, however analogues with Gram-negative activity often suffer from hERG channel inhibition. A novel series of bicyclic-oxazolidinone inhibitors of Bacterial type II Topoisomerase were identified which display potent broad-spectrum anti-bacterial activity, including against MDR strains, along with an encouraging in vitro safety profile. In vivo proof of concept was achieved in a A. baumannii mouse thigh Infection model.

Keywords

Anti-infectives; DNA gyrase; ESKAPE pathogens; NBTI; Oxazolidinone; Topoisomerases.

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