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

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• Antibiotic resistance is a critical global health threat requiring novel therapeutic approaches.
• Bacterial metalloproteins, particularly in iron uptake and manganese-based oxidative defense, are emerging targets for antimicrobial development.
• The precise biological roles of many metals and metal-containing compounds in antimicrobial activity require further elucidation.

Purpose of the Study:

• To review and critically evaluate translational strategies for targeting bacterial metalloproteins.
• To explore the potential of metallodrugs as selective and less toxic alternatives to conventional antibiotics.
• To identify key challenges and future research directions in this field.

Main Methods:

• Comprehensive literature synthesis integrating evidence from multiple databases.
• Narrative synthesis combined with systematic methodology.
• Critical evaluation of translational strategies including siderophore-antibiotic conjugates, metal trafficking inhibitors, and catalytic metallodrugs.

Main Results:

• Targeting bacterial metalloproteins involved in siderophore-mediated iron uptake and manganese-based oxidative defense shows potential for novel antibacterial drug development.
• Siderophore-antibiotic conjugates, metal trafficking inhibitors, and catalytic metallodrugs represent viable therapeutic strategies.
• Receptor-mediated uptake and genomic data-guided therapies are recommended for priority clinical development.

Conclusions:

• Targeting bacterial metalloproteins presents a promising avenue for developing novel, selective, and less toxic antibacterial agents to combat resistance.
• Further research is needed to address challenges in selectivity, toxicity, and bacterial resistance mechanisms.
• A strategic approach prioritizing receptor-mediated uptake and genomic data is crucial for advancing metallodrugs into clinical practice.