Targeting multi-drug resistant pathogens with synergistic beta-lactams and beta-lactam inhibitor combinations

Background: Infections caused by multidrug-resistant organisms pose a significant global health challenge due to the limited therapeutic options available. Synergistic drug combinations are often employed to enhance treatment efficacy. Because peptidoglycan is unique to prokaryotes, many studies focus on combinations that include beta-lactam antibiotics. To address bacterial strains that produce beta-lactamases, a range of beta-lactamase inhibitors has been developed. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI) regularly update clinical guidelines to include standards for new beta-lactam/beta-lactamase inhibitor combinations. Objective: This work provides an overview of beta-lactam and beta-lactamase inhibitor combinations, together with updated clinical guidelines and an analysis of the relevant Protein Data Bank (PDB) entries related to these synergistic combinations. First, the latest EUCAST and CLSI guidelines are reviewed to identify the most recent beta-lactam/beta-lactamase inhibitor combinations used in therapy. Next, PDB entries related to these combinations are examined and compared with new compounds under investigation. EUCAST and CLSI guidelines are valuable for guiding therapeutic strategies, not only for interpreting antibiograms. The newest beta-lactamase inhibitors include avibactam, relebactam, vaborbactam, and enmetazobactam. X-ray crystallography studies have enhanced understanding of inhibitor interactions with major beta-lactamases in Gram-negative pathogens—serine beta-lactamases and metallo-beta-lactamases. Conclusion: Investigating synergistic combinations of beta-lactams and beta-lactamase inhibitors is promising because beta-lactams target peptidoglycan and may enable new therapeutic strategies.