Evaluation Of Medicines For Malaria Venture (Mmv) Compound Library For Potency Against P. Falciparum Clinical Isolates

Abstract

The resistance of Plasmodium falciparum to artemisinin and its derivatives underscore the need for new sets of antimalarials with novel mechanisms of action. Towards the development of new, affordable and easily accessible antimalarial drugs for endemic regions, there is the need to screen more compounds for their antimalarial activity. Several studies on different compound classes have been conducted using laboratory strains of P. falciparum. However, not much is known of their potency on clinical isolates. In this study, an optimal in vitro growth inhibitory assay was established and used to screen ten selected compounds from the Malaria Box against four clinical isolates from three endemic areas in Ghana (Accra-two, Navrongo-one and Kintampo-one). From the assays, MMV085203, MMV006787 and MMV008956 were found to have IC50 values below 500 nM with the most efficacious being MMV085203 (IC50 values between 55 nM-83 nM). MMV006787 was also found to be more potent against the clinical isolates compared to its activity against laboratory strain of P. falciparum, as was reported by previous studies. The Navrongo isolate (N093) was more sensitive to artesunate and most of the Malaria Box compounds but resistant to chloroquine. Genomic studies using restriction fragment length polymorphism (RFLP) identified N093 to harbour the mutant pfcrt allele (T76) while the other three had the wild-type pfcrt allele (K76). Therefore, the presence of the K76T mutation in N093 seems to confirm data from other studies that suggest that the presence of this mutation increases the sensitivity of malaria parasites to artemisinin-based drugs and resistance to chloroquine. The use of clinical isolates in this study further demonstrates the need to validate potential drug compounds using clinical isolates in addition to the use of laboratory-adapted strains for drug development.