Metal-Ligand Interactions: Overlooked Confounders in Antibiotic Discovery and Development

Area of Science:

• Pharmaceutical Science
• Medicinal Chemistry
• Drug Development

Background:

• Antimicrobial resistance (AMR) is a growing global health crisis, necessitating the development of novel antibiotics.
• Antibiotic development faces significant hurdles, including insufficient investment and financial incentives.
• Metal ion interference in assays and pharmacokinetic studies is an underappreciated factor complicating antibiotic development.

Purpose of the Study:

• To highlight the impact of metal interference as a confounder in antibiotic development.
• To propose a framework for anticipating and addressing metal interference.
• To provide practical toolkits for identifying metal interference in antibiotic research.

Main Methods:

• A compartment-based approach is presented to model potential metal interference.
• Literature review and expert knowledge synthesis to identify common metal interference points.
• Recommendations for experimental toolkits and strategies for detection.

Main Results:

• Metal interference can affect high-throughput screening, mechanism of action studies, and pharmacokinetic profiling.
• A systematic approach can predict and identify specific instances of metal interference.
• Practical methods and tools are available to detect and manage metal ion effects.

Conclusions:

• Addressing metal interference is crucial for improving the efficiency and success rate of antibiotic development.
• Implementing standardized methods to assess metal ion effects can save resources and accelerate the discovery of effective antibiotics.
• Proactive management of metal interference is essential to combat the rising threat of antimicrobial resistance.