Efficacy and mechanism of action of cipargamin as an antibabesial drug candidate.

Abstract

Babesiosis is a disease brought on by intraerythrocytic parasites of the genus. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs against. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainlyand. This study evaluated the growth-inhibiting properties of CIP againstspp. and investigated the mechanism of CIP on. The half inhibitory concentration (IC) values of CIP against the in vitro growth ofandwere 20.2 ± 1.4 and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth ofandin vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3- and 2.4-fold decrease in BgATP4and BgATP4, respectively, compared to that of BgATP4. An in silico investigation revealed reductions in affinity for CIP binding to BgATP4and BgATP4compared to BgATP4. Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in ICvalues. Combining CIP with TQ effectively eliminatedinfection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.