N-Aryl-2-iso-butylmercaptoacetamides: the discovery of highly potent and selective inhibitors of Pseudomonas aeruginosa virulence factor LasB and Clostridium histolyticum virulence factor ColH

Abstract

Antimicrobial resistance is currently one of the serious global public health threats. Unlike the conventional antimicrobial drugs, antivirulence agents disarm rather than kill bacterial pathogens and therefore represent an alternative option to skirt the problem of resistance. Pseudomonas aeruginosa elastase (LasB) and Clostridium histolyticum collagenase (ColH) are extracellular bacterial proteases which play a critical role in the establishment and progression of the respective bacterial infection. In this study, we report the modulation of the α-position of the previously reported N-aryl mercaptoacetamide class leading to a new type of highly potent LasB and ColH inhibitors (N-aryl-2-iso-butylmercaptoacetamides). In addition to their non-toxicity and high selectivity over several human off-targets, selected derivatives may be considered unprecedented dual inhibitors of both LasB and ColH. Among the prepared derivatives, compound 37 showed the most promising properties: it had a favorable safety profile, maintained the viability and integrity of both skin- and lung-cells treated with P. aeruginosa supernatant, demonstrated in vivo efficacy in Galleria mellonella larvae, and revealed a good volume of distribution and moderate in vivo clearance in mice. Taking together, these results demonstrate that compound 37 is a promising candidate for antivirulence drug development.