Preliminary efficacy of anthelmintic closantel as a potential antimicrobial against Gram-positive bacteria: An assessment of the enantioselectivity

OBJECTIVES: Approved salicylamide agents exhibit promising activity against multidrug-resistant Gram-positive bacteria (GPB). The objectives of this study were to investigate whether the antimicrobial efficacy of closantel (CLO) is related to its enantiomeric properties, and whether the CLO enantiomers contribute the efficacy significantly. METHODS: The in vitro antibacterial activities of R-CLO and S-CLO against staphylococcus and enterococcus were explored using minimum inhibitory concentrations, growth inhibition curves, time-killing assays, and postantibiotic effects. The potential effects of enantiomers were investigated by a series of validated assays, and subsequently in vivo therapeutic potential was assessed in murine models of skin abscess and peritoneal infection. RESULTS: R-CLO and S-CLO displayed promising antibacterial properties in vitro, comparable to CLO. Their activities were potentially associated with alterations in cell membrane morphology, loss of membrane integrity, changes in membrane potential, and inhibition of biofilm formation in a concentration-dependent manner, as well as interference with intracellular ATP synthesis and accumulation of ROS in a concentration-independent manner. Compared with the untreated group, R-CLO could effectively reduce bacterial load of skin abscess and peritoneal infection in mice at each time point and reached statistical significance (P < 0.05); however, the S-CLO exhibited a comparatively lower performance. They also provided a degree of protection at the single intraperitoneal injection of 10 mg/kg body weight, achieving survival rates of 30% and 20%, respectively, and showing no statistical difference (log-rank test, P > 0.05). CONCLUSIONS: These preliminary findings suggest that both enantiomers are effective as monotherapy and contribute to the promising antimicrobial activity of CLO against GPB.