FPI-1523, a novel β-lactamase inhibitor, enhances imipenem activity against carbapenemase-producing Enterobacterales.

OBJECTIVE

Evaluating the in vitro and in vivo antimicrobial activity of FPI-1523, a novel β-lactamase inhibitor, in combination with imipenem against carbapenemase-producing carbapenem-resistant Enterobacterales (CRE).

METHODS

The in vitro and in vivo antibacterial effect of FPI-1523 combined with imipenem against CRE strains were evaluated using antimicrobial susceptibility test, time-kill assays, and Galleria mellonella infection model. Haemolysis assays and cytotoxicity experiments were performed to evaluate the safety. Modified carbapenem inactivation method and carbapenemase inhibition assay of crude periplasmic extract were conducted to explore the mechanistic basis of the antibacterial effect of the FPI-1523 and imipenem combination.

RESULTS

Combined with FPI-1523, the majority of these strains (21/28, 75%) regained susceptibility to imipenem (MIC ≤ 1 mg/L), including those producing KPC, NDM, and IMP carbapenemases. Further analysis revealed that FPI-1523 exhibited intrinsic antimicrobial activity against Enterobacter cloacae and Escherichia coli, with MIC values ranging from 2 to 128 mg/L. These in vitro significant antibacterial effects were further confirmed by time-kill assays. The in vivo significant antibacterial effects were validated using a G. mellonella infection model. Haemolysis assays and cytotoxicity tests confirmed the safety of the drug combination. Modified carbapenem inactivation method and carbapenemase inhibition assay of crude periplasmic extract revealed that FPI-1523 effectively inhibited carbapenemase (excluding class B carbapenemases) activity. Based on the antimicrobial susceptibility results, for class B carbapenemase-producing strains, the antibacterial effect may be primarily mediated by FPI-1523 monotherapy.

CONCLUSIONS

The combination of FPI-1523 and imipenem demonstrates significant antibacterial activity against diverse carbapenemase-producing CRE.