β-lactamase inhibitors: a promising strategy for restoring carbapenem effectiveness

Carbapenems are widely used antimicrobial agents, particularly in treating hospital -acquired infections caused by drug-resistant Gram-negative pathogens. The emergence and growing prevalence of carbapenem-resistant bacteria have reduced the effectiveness of these antibiotics. Enzymatic degradation is the primary mechanism of resistance to carbapenems. A variety of enzymes with carbapenemase activity has been identified, which are assigned to serine β-lactamase (SBLs) and metallo-β-lactamase (MBLs) groups based on their mode of action. Inactivating carbapenemases could theoretically improve the efficacy of carbapenems in treating carbapenem-resistant strains. This review focuses on carbapenem-inhibitor combinations, highlighting both natural and synthetic inhibitors that are currently under investigation. Their effectiveness has been observed in both in vitro and in vivo studies when used in combination with carbapenems against various bacteria. Some studies on β-lactamase inhibitors have progressed to the clinical phases, while others are still in the early stages of in vitro testing. The use of certain inhibitors, particularly MBL inhibitors, is restricted because of the lack of selective toxicity and their inhibitory effects on metalloenzymes in eukaryotic cells. The purpose of this study is to review the existing in vitro and in vivo data regarding the effectiveness, challenges, advancements, and uses of new β-lactamase inhibitors that target carbapenemases.