Multiple-stage active antimalarial, Cabamiquine, inhibits multiple real-world Plasmodium species with no cross resistance with existing treatments

Malaria remains a major public health concern in Sub-Saharan Africa. The widespread and emerging drug resistance call for urgent development of new drugs with novel modes of action to treat, control, and eliminate malaria. Cabamiquine, a promising antimalarial drug candidate that inhibits protein synthesis, has demonstrated promising potency across multiple life stages of P. falciparum. Here, in in Ghana and in Mali, we assessed the ex-vivo susceptibility to cabamiquine of non- falciparum malaria field isolates of P. ovale and P. malariae compared to P. falciparum and explored the drug candidate potential cross-resistance with existing antimalarial drug. Thus, cabamiquine susceptible and selected resistant P. falciparum laboratory strains and clinical isolates were tested to a panel of antimalarial drugs.P. ovale isolates displayed a decreased susceptibility to DHA when compared to P. falciparum (p = 0.0371), but no significant difference was noticed for Cabamiquine against both species. Conversely, P. malariae isolates were less susceptible to Cabamiquine than P. falciparum (p = 0.001), while there was no significant difference in susceptibility to DHA both for P. malariae and P. falciparum isolates. The mutant parasites’ susceptibility to amodiaquine, tafenoquine, sulfadoxine, pyrimethamine, pyronaridine, and des-ethylamodiaquine, was like the wild-types susceptibility (WT). However, there was a non-significant trend to higher IC_50s in the mutant strains than the WT for lumefantrine, pyrimethamine, chloroquine, primaquine, and quinine. Overall, the results on P. ovale and P. malariae susceptibility to cabamiquine indicated this drug candidate potential to target diverse Plasmodium species to accelerate malaria elimination. Through this study, it was also demonstrated, no cross-resistance of cabamiquine drug candidate with various existing antimalarial drugs and thus, novel cabamiquine can be combined with some of them to delay it drug resistance emergence and spread.