From Microbes to Medicine: Targeting Metalloprotein Pathways for Innovative Antibacterial Strategies

Antibiotic resistance poses a growing global health crisis, demanding innovative therapeutic strategies beyond traditional drug classes. This review hypothesizes that selective targeting of bacterial metalloprotein pathways—particularly siderophore-mediated iron acquisition and manganese-dependent oxidative defense—offers the most promising route to narrow-spectrum antibacterial agents with reduced host toxicity. Metals and metal-containing compounds are increasingly recognized for their potent antimicrobial properties and underexplored biochemical roles. By synthesizing current evidence, this article critically evaluates translational strategies including siderophore–antibiotic conjugates, metal trafficking inhibitors, and catalytic metallodrugs. It argues that receptor-mediated uptake and mechanism-informed designs supported by genomic context should be prioritized for clinical development. The review also highlights unresolved challenges in selectivity, toxicity, and resistance mechanisms, offering a roadmap for future research. This manuscript is prepared as a narrative review with systematic elements, integrating evidence from multiple databases to provide a comprehensive framework for targeting bacterial metalloproteins.