Discovery of New Microbial Collagenase Inhibitors

SIMPLE SUMMARY: Antimicrobial resistance is spreading globally, making healthcare specialists fear “a return to the dark age of medicine”. Great efforts are being made to develop new antimicrobials or to repurpose discontinued or shelved drugs to be used against resistant “superbugs”. Resistance occurs partly because the antibiotics we use kill the bacteria. However, this also induces a high selection pressure: a resistant bacterium will multiply, while its non-resistant competitors will die. Thus, resistance will develop rapidly in the presence of that antibiotic. An alternative is simply disarming bacteria—reducing their ability to infect the host. In other words, we should develop drugs that inhibit bacterial virulence rather than bacterial viability. Bacterial virulence factors such as collagenases emerged as attractive targets for overcoming antimicrobial resistance. Microbial collagenases digest host collagen, ensuring the spread of the pathogen and its toxins into host tissues. In this study, we aimed to identify plant-derived and repurposed drugs which potently inhibit collagenase A. We achieved this by performing extensive screening. We identified capsaicin, 4′,5-dihydroxyflavone, curcumin, dihydrorobinetin, palmatine chloride, biochanin A, 2′-hydroxychalcone, and juglone as promising collagenase inhibitors. Our data indicate these molecules could be used against infections caused by multi-drug-resistant bacterial pathogens which express collagenase A. ABSTRACT: Bacterial virulence factors are mediating bacterial pathogenesis and infectivity. Collagenases are virulence factors secreted by several bacterial stains, such as Clostridium, Bacillus, Vibrio and Pseudomonas. These enzymes are among the most efficient degraders of collagen, playing a crucial role in host colonization. Thus, they are an important target for developing new anti-infective agents because of their pivotal roles in the infection process. A primary screening using a fluorescence resonance energy-transfer assay was used to experimentally evaluate the inhibitory activity of 77 compounds on collagenase A. Based on their inhibitory activity and chemical diversity, a small number of compounds was selected to determine the corresponding half maximal inhibitory con-centration (IC50). Additionally, we used molecular docking to get a better understanding of the enzyme–compound interaction. Several natural compounds (capsaicin, 4′,5-dihydroxyflavone, curcumin, dihydrorobinetin, palmatine chloride, biochanin A, 2′-hydroxychalcone, and juglone) were identified as promising candidates for further development into useful anti-infective agents against infections caused by multi-drug-resistant bacterial pathogens which include collagenase A in their enzymatic set.