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
  • 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: [email protected].
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.