In-vitro and in-vivo efficacy of a novel broad spectrum β-lactamase inhibitor APC24-7 against Enterobacterales

Abstract

The rise of multidrug-resistant (MDR) bacteria, particularly carbapenem-resistant Enterobacterales (CRE), poses a significant threat to public health. Infections caused by CRE, such as Escherichia coli and Klebsiella pneumoniae, are associated with high rates of antibiotic treatment failure. {beta}-lactam antibiotics, like meropenem, remain crucial in treating these infections, but their efficacy is undermined by {beta}-lactamase production. This study investigates the potential of APC24-7, a novel broad-spectrum {beta}-lactamase inhibitor (BLi) with dual activity, to restore antimicrobial activity of meropenem against CRE clinical isolates. The in-vitro analysis of a diverse panel of clinically relevant E. coli and K. pneumoniae isolates expressing both serine- and metallo-{beta}-lactamases demonstrated that APC24-7 effectively restored meropenem activity by reducing the minimum inhibitory concentrations (MICs) to below breakpoint. Time-kill assays confirmed that the combination therapy showed dose-dependent bacterial killing, with significant potentiation of meropenem activity against isolates expressing both serine- and metallo-{beta}-lactamases. In-vivo efficacy evaluation in a murine thigh infection model further confirmed APC24-7s potential to restore meropenem efficacy against meropenem resistant strains. These findings suggest that APC24-7offers a promising strategy to combat infections caused by {beta}-lactamase-producing Enterobacterales.