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

Abstract

There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.

Keywords: Anti-infectives; DNA gyrase; ESKAPE pathogens; Isothiazolone; Topoisomerases.