In Vitro and In Vivo Development of a β-Lactam-Metallo-β-Lactamase Inhibitor: Targeting Carbapenem-Resistant...

Area of Science:

• Medicinal Chemistry
• Antimicrobial Resistance
• Drug Discovery

Background:

• β-lactam antibiotics are crucial but threatened by resistance, particularly from carbapenem-resistant Enterobacterales expressing metallo-β-lactamases (MBLs).
• Effective treatments are urgently needed to restore carbapenem efficacy against MBL-producing bacteria.

Purpose of the Study:

• To develop and evaluate a novel therapeutic agent, BP1, designed to inhibit MBLs and restore carbapenem antibiotic activity.
• To assess the in vitro and in vivo efficacy, as well as the safety profile, of BP1.

Main Methods:

• BP1, a cyclic zinc chelator attached to a cephalosporin scaffold, was tested against MBL-expressing bacteria.
• In vitro assays evaluated meropenem restoration, MBL inhibition (VIM-2, NDM-1), and cytotoxicity.
• In vivo studies assessed BP1 efficacy in a mouse model of Klebsiella pneumoniae infection.

Main Results:

• BP1 restored meropenem efficacy to ≤ 0.5 mg/L with sterilizing activity within 8 hours.
• BP1 showed potent inhibition of VIM-2 (K_i 24.8 μM) and NDM-1 (K_i 97.4 μM) without affecting human glyoxylase II.
• BP1 was nontoxic to human cells (IC₅₀ > 1000 mg/L) and reduced bacterial load by >3 log₁₀ in infected mice when combined with meropenem.

Conclusions:

• BP1 is a promising MBL inhibitor that restores carbapenem efficacy.
• This compound offers a potential therapeutic strategy to combat carbapenem-resistant Enterobacterales and curb antimicrobial resistance.