Inhibition and activity regulation of bacterial collagenases

Abstract

The imminent antimicrobial resistance dilemma requests for drug discovery initiatives outside the box of classical antibiotics strategies, including the identification of anti-virulence targets. Given their critical roles in diverse infectious diseases, bacterial collagenases constitute one such class of anti-virulence targets. Here we review the essential catalytic elements of bacterial collagenases, including the zinc-coordinating residues, as well as their typical domain organization with relevance to collagenolysis. We further present the structural basis for the substrate specificities, both towards linear and triple-helical peptides. These enzymatic properties shape the structural framework for the discovery and development of competitive, active site-directed inhibitors. While currently available compounds bind the catalytic zinc, alternative interaction possibilities at the active site promise an improved specificity towards other metalloproteases. We finally outline inhibition opportunities that result from exploiting collagenase exosites.