Navigating the complexities of drug development for metallo-β-lactamase inhibitors

The rising antibiotic resistance rates, especially among carbapenem-resistant Enterobacterales with metallo-β-lactamases (MBLs), highlight the urgent need for effective MBL inhibitors (MBLIs). Navigating the complexities of drug development for MBLIs requires addressing the significant challenges that have hindered its progress. Despite numerous efforts in pre-clinical development, the lack of standardized approaches has led to disparities, stalling the translation of potential MBLIs from research into clinical use. Alarmingly, there is only one metallo-β-lactamase inhibitory candidate in the pre-registration phase of development. This review highlights the need for a global consensus on key aspects of MBLI development, including standardized in vitro testing, refined animal models, harmonized toxicity assessments, consistent pharmacokinetic data, and uniform in silico methods. It also proposes solutions to these challenges, aiming to bridge the gap between research and clinical application.