Antibacterial and Antibiofilm Activity of Closantel Against <i>Staphylococcus epidermidis</i>

Staphylococcus epidermidis is recognized as the major cause of implanted indwelling medical device-related infections. The ability of S. epidermidis to form biofilms largely increases its resistance to conventional antibiotics, which is the major cause of treatment failure. Therefore, there is a pressing need to discover novel antimicrobials against S. epidermidis biofilms. In this study, Closantel (Clos), an antiparasitic drug, was repurposed to be effective against S. epidermidis planktonic cells with the minimal inhibitory concentration values of 0.25-0.5 μg/mL. Clos exhibited potent biofilm inhibition at ≥ 0.5 μg/mL and achieved effective eradication at ≥ 1 μg/mL. Notably, Clos induced lower resistance in S. epidermidis compared to Rifampicin. Mechanism study indicated that Clos exerted the bactericidal activity mainly through inducing bacterial cell membrane depolarization and further disruption. And the antibiofilm activity of Clos could be partially due to the inhibition of initial adhesion and extracellular polysaccharides production. In addition, CCK-8 assay showed that Clos at 16 μg/mL had limited cytotoxicity in A2780, HaCaT and 293 T cells. In conclusion, this study demonstrates that Clos, a molecule targeting bacterial cell membranes, exhibits strong antimicrobial and antibiofilm effects in vitro against S. epidermidis. Although, side effects were reported in mammals, developing Clos derivatives could be still an effective therapeutic strategy to treat S. epidermidis-related infections.