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

Antibiotic resistance is an escalating global health problem that calls for new types of treatments beyond standard antibiotics. This review examines how targeting bacterial metalloproteins, especially those involved in siderophore-driven iron uptake and manganese-based oxidative defense, could lead to more selective antibacterial drugs that are less toxic to humans. Recent research shows that metals and metal-containing compounds can act as antimicrobials, but many of their biological roles are still not well understood. By synthesizing current evidence, this article critically evaluates translational strategies targeting bacterial metalloproteins. These include siderophore–antibiotic conjugates, metal trafficking inhibitors, and catalytic metallodrugs. The review suggests that therapies using receptor-mediated uptake and guided by genomic data deserve priority in clinical development. The review also highlights unresolved challenges in selectivity, toxicity, and resistance mechanisms, offering a roadmap for future research. This review integrates evidence from multiple databases to provide a comprehensive framework for targeting bacterial metalloproteins, combining narrative synthesis with systematic methodology.