Efficacy and mechanism of actions of cipargamin as an antibabesial drug candidate

Babesiosis is a disease brought on by intraerythrocytic parasites of the genusBabesia. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs againstBabesia. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainlyPlasmodiumandToxoplasma. This study evaluated the growth-inhibiting properties of CIP againstBabesiaspp. and investigated the mechanism of CIP onB. gibsoni. The half inhibitory concentration (IC₅₀₎values of CIP against thein vitrogrowth ofB. bovisandB. gibsoniwere 20.2 ± 1.4 nM and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth ofB. microtiandB. rodhaini in vivo.Resistance was conferred by L921V and L921I mutations inBgATP4, which reduced the sensitivity to CIP by 6.1-and 12.8-fold. Anin silicoinvestigation revealed reductions in affinity for CIP binding toBgATP4^L921VandBgATP4^L921Icompared toBgATP4^WT. In this study, we characterized the efficacy of CIP againstBabesiaspp. by investigating the mechanistic basis for the resistance to CIP conferred by mutations in theBgATP4. Our findings present a promising starting point for the establishment of new therapeutic interventions againstBabesiainfection.