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

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 (IC50) 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 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-fold and 2.4-fold decrease in
BgATP4L921V and BgATP4L921I, respectively, compared to that of BgATP4WT.
An in-silico investigation revealed reductions in affinity for CIP binding
to BgATP4L921V and BgATP4L921I compared to BgATP4WT. Resistant strains
showed no significant cross-resistance to atovaquone (ATO) or tafenoquine
succinate (TQ), with less than a one-fold change in IC50 values. Combining
CIP with TQ effectively eliminated B. microti infection 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
anti-babesial 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.