MBL-IN-5 is an inhibitor of metallo-β-lactamase (MBL). It effectively suppresses three clinically significant B1 subfamily MBLs: NDM-1, VIM-1, and IMP-1 with IC50 values of 0.05 nM, 14 nM, and 21 nM respectively. MBL-IN-5 notably enhances the efficacy of carbapenem antibiotics against MBL-producing clinical strains and, when combined with IPM antibiotics, significantly reduces bacterial load in a thigh infection model.

NDM1:0.05 nM

MBL-IN-5 (Compound 17u) exhibits strong synergy with Imipenem (IPM) and Meropenem against carbapenem-resistant Klebsiella pneumoniae ATCC BAA-2146 expressing New Delhi Metallo-beta-lactamase-1 (NDM-1) at concentrations of 4-32 μg/mL over 16-18 hours. At 3.12-50 μM, MBL-IN-5 significantly stabilizes NDM-1, causing a positive shift in Tm of approximately 15-20 °C. The compound displays optimal ADME properties with moderate solubility, high permeability, and moderate clearance at concentrations of 1-500 μM. Inhibiting NDM-1 effectively at 0.5-16 μg/mL over 16-18 hours, MBL-IN-5 restores the sensitivity of tested ATCC strains to Meropenem and IPM, and shows high inhibition of NDM-1 expressing Enterobacteriaceae clinical strains when combined with these antibiotics. MBL-IN-5 has greater specificity for MBL over MMP, with IC50 values for MMP-1, MMP-2, and MMP-9 at >120 μM, 2.9 μM, and 45 μM respectively.

When used in combination with IPM, MBL-IN-5 (Compound 17u) (20-50 mg/kg, subcutaneous injection, every 8 hours for a total of 3 doses) significantly enhances IPM's effectiveness against NDM-1 expressing, carbapenem-resistant Klebsiella pneumoniae ATCC BAA 2146 in a neutropenic mouse thigh infection model and reduces bacterial load.