Discovery and structure–activity relationships of a novel oxazolidinone class of bacterial type II topoisomerase inhibitors. (1st June 2022)

• Record Type: Journal Article
• Authors: Lyons, Amanda; Kirkham, James; Blades, Kevin; Orr, David; Dauncey, Elizabeth; Smith, Oliver; Dick, Emma; Walker, Rolf; Matthews, Teresa; Bunt, Adam; Finlayson, Jonathan; Morrison, Ian; Savage, Victoria J.; Moyo, Emmanuel; Butler, Hayley S.; Newman, Rebecca; Ooi, Nicola; Smith, Andrew; Charrier, Cédric; Ratcliffe, Andrew J.; Stokes, Neil R.; Best, Stuart; Salisbury, Anne-Marie; Craighead, Mark; Cooper, Ian R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 65(2022)
• Publication Date: 2022-06-01
• Subjects: ESKAPE pathogens -- Anti-infectives -- Topoisomerases -- DNA gyrase -- NBTI -- Oxazolidinone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128648
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.