Repurposing cinacalcet suppresses multidrug-resistant Staphylococcus aureus by disruption of cell membrane and inhibits biofilm by targeting IcaR

Abstract Background MDR Staphylococcus aureus infections, along with the severity of biofilm-associated infections, continue to threaten human health to a great extent. It necessitates the urgent development of novel antimicrobial and antibiofilm agents. Objectives To reveal the mechanism and target of cinacalcet as an antibacterial and antimicrobial agent for S. aureus. Methods Screening of non-antibiotic drugs for antibacterial and antibiofilm properties was conducted using a small-molecule drug library. In vivo efficacy was assessed through animal models, and the antibacterial mechanism was studied using quantitative proteomics, biochemical assays, LiP-SMap, BLI detection and gene knockout techniques. Results Cinacalcet, an FDA-approved drug, demonstrated antibacterial and antibiofilm activity against S. aureus, with less observed development of bacterial resistance. Importantly, cinacalcet significantly improved survival in a pneumonia model and bacterial clearance in a biofilm infection model. Moreover, the antibacterial mechanism of cinacalcet mainly involves the destruction of membrane-targeted structures, alteration of energy metabolism, and production of reactive oxygen species (ROS). Cinacalcet was found to target IcaR, inhibiting biofilm formation through the negative regulation of IcaADBC. Conclusions The findings suggest that cinacalcet has potential for repurposing as a therapeutic agent for MDR S. aureus infections and associated biofilms, warranting further investigation.