Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Emergence of virulent Enterobacterales strains expressing serine and metallo-β-lactamase (MBL) genes leads to resistance against antibiotics.
• Existing serine β-lactamase inhibitors (SBLIs) are in use, but a critical need for metallo-β-lactamase inhibitors (MBLIs) is unmet.

Purpose of the Study:

• To evaluate the efficacy of BP2, a novel beta-lactam-derived inhibitor, when co-administered with meropenem against MBL-producing Enterobacterales.
• To assess the safety and specific binding of BP2 to metallo-β-lactamases.

Main Methods:

• Antimicrobial susceptibility testing to determine minimum inhibitory concentrations (MICs).
• Enzyme inhibition kinetics to evaluate binding affinity (K_app) against NDM-1 and VIM-2.
• In vivo efficacy study using a murine infection model with *K. pneumoniae* NDM.

Main Results:

• BP2 potentiated meropenem's activity to an MIC of ≤1 mg/L, demonstrating synergistic effects.
• BP2 exhibited bactericidal activity over 24 hours and was safe at tested concentrations.
• BP2 showed specific inhibition of NDM-1 (K_app = 35.3 µM) and VIM-2 (K_app = 30.9 µM) without interacting with glyoxylase II.
• Co-administration of BP2 and meropenem significantly reduced bacterial load in a murine thigh infection model (>3 log₁₀ reduction).

Conclusions:

• BP2 demonstrates potent synergistic activity with meropenem against MBL-producing bacteria.
• The compound is bactericidal, safe, and specifically targets metallo-β-lactamases.
• BP2 represents a promising candidate for further development as a metallo-β-lactamase inhibitor (MBLI).