Repurposing insights: experimental and pharmacological approach on L-captopril and dimercaprol as metallo-β-lactamase inhibitors

Abstract

The design of specific inhibitors of metallo-β-lactamases (MBL) is one of the priority research lines due to the spread of carbapenem resistant bacterial strains which limits therapeutic options. In parallel, the investigation of new uses of known medicines is prompted by regulatory agencies. In this work, the potential MBL inhibitory potency of L-captopril (an antihypertensive drug) and dimercaprol (used in poisoning by metals) was investigated in a clinical collection of Enterobacterales and Pseudomonas spp. In addition, a comprehensive review of the available literature was conducted, to discuss jointly new and previously available data. The results indicate that activity of imipenem and meropenem combined with 400 mg/l is restored for > 80% and 60%, respectively, for Enterobacterales strains, but not in the Pseudomonas group. Dimercaprol had a limited activity in both bacterial groups. Based on these promising results of L-captopril, pharmacological calculations were performed. It is concluded that the repurposing objective could not be achieved as the overall data indicated that the concentrations of captopril required to achieve carbapenemase inhibitory activity in vivo are higher than maximum used in treatment. Communication of negative results would help to discontinue active current research on L-captopril and should focus on other potential MBL inhibitors.