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

Abstract

Babesiosis is a disease brought on by intraerythrocytic parasites of the genus Babesia . Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs against Babesia . Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainly Plasmodium and Toxoplasma . This study evaluated the growth-inhibiting properties of CIP against Babesia spp. and investigated the mechanism of CIP on B. gibsoni . The half inhibitory concentration (IC 50) values of CIP against the in vitro growth of B. bovis and B. gibsoni were 20.2 ± 1.4 nM and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth of B. microti and B. rodhaini in vivo. Resistance was conferred by L921V and L921I mutations in Bg ATP4, which reduced the sensitivity to CIP by 6.1-and 12.8-fold. An in silico investigation revealed reductions in affinity for CIP binding to Bg ATP4 L921V and Bg ATP4 L921I compared to Bg ATP4 WT . In this study, we characterized the efficacy of CIP against Babesia spp. by investigating the mechanistic basis for the resistance to CIP conferred by mutations in the Bg ATP4. Our findings present a promising starting point for the establishment of new therapeutic interventions against Babesia infection.