<i>N</i>-Aryl-3-mercaptosuccinimides as Antivirulence Agents Targeting <i>Pseudomonas aeruginosa</i> Elastase and <i>Clostridium</i> Collagenases

Abstract

In light of the global antimicrobial-resistance crisis, there is an urgent need for novel bacterial targets and antibiotics with novel modes of action. It has been shown that <i>Pseudomonas aeruginosa</i> elastase (LasB) and <i>Clostridium histolyticum</i> (<i>Hathewaya histolytica</i>) collagenase (ColH) play a significant role in the infection process and thereby represent promising antivirulence targets. Here, we report novel <i>N</i>-aryl-3-mercaptosuccinimide inhibitors that target both LasB and ColH, displaying potent activities <i>in vitro</i> and high selectivity for the bacterial over human metalloproteases. Additionally, the inhibitors demonstrate no signs of cytotoxicity against selected human cell lines and in a zebrafish embryo toxicity model. Furthermore, the most active ColH inhibitor shows a significant reduction of collagen degradation in an <i>ex vivo</i> pig-skin model.