MECHANISMS OF DRUG RESISTANCE IN PLASMODIUM SPECIES

Abstract

P. vivax, the most widespread human malaria parasites with high morbidity, presents persistent challenges due to unpredictable hypnozoites relapses and drug resistance. In the Investigation of novel therapeutics like DDD107498, we utilise P. cynomolgi, a sister taxon to P. vivax, as a surrogate model for assessing antimalarial efficacy. Employing forward and reverse genetics, we identify distinct resistance mechanisms in DDD107498-resistant P. cynomolgi, differing from those in P. falciparum. These resistant variants exhibit reduced fitness, and the engineering of a key mutation identified on P. falciparum elongation factor 2 (Y186N) in the ortholog of P. cynomolgi using CRISPR-Cas9 resulted in resistance under prolonged drug pressure. Our study unveils a unique drug resistance mechanism in P. cynomolgi, emphasizing unique drug resistance between the related species.