Bacterial zinc metalloproteases as facilitators of pathogenic success: a review

Zinc metalloproteases are pivotal catalytic enzymes that facilitate zinc-dependent selective cleavage of peptide bonds within proteins. Zinc metalloproteases are widely distributed across bacterial species, particularly pathogens, where they act as multifaceted virulence factors. Bacillus anthracis produces the zinc metalloproteases Lethal Factor (LF), InhA1, and Npr599, which exhibit versatile host-targeting activities, including disruption of immune responses, facilitation of bacterial dissemination and tissue invasion, and modulation of the bacterial secretome. GelE, from Enterococcus faecalis, regulates biofilm formation, bacterial adherence and dissemination, and expedites host invasion and inflammation. Burkholderia cenocepacia's ZmpB contributes to antimicrobial tolerance and nutrient acquisition, whereas in Mycobacterium tuberculosis, Zmp1 mediates immunomodulatory functions, whilst Rip1 regulates intramembrane proteolysis and activates stress response pathways. This review consolidates current knowledge on bacterial zinc metalloproteases and their roles in disease, and advocates for comprehensive research that holistically elucidates zinc metalloproteases, as such integrated understanding is essential for their effective application as therapeutic targets.