Genetic complexity alters drug susceptibility of asexual and gametocyte stages of Plasmodium falciparum to antimalarial candidates

Abstract

Malaria elimination requires interventions able to target both the asexual blood stage (ABS) parasites and transmissible gametocyte stages of Plasmodium falciparum. Lead antimalarial candidates are evaluated against clinical isolates to address key concerns regarding efficacyand to confirmthat the current, circulating parasites from endemic regions lack resistance against these candidates. While this has largely been performed on ABS parasites, limited data are available on the transmission-blocking efficacyof compounds with multistage activity. Here, we evaluated the efficacyof lead antimalarial candidates against both ABS parasites and late-stage gametocytes side-by-side, against clinical P. falciparum isolates from southern Africa. We additionally correlated drug efficacyto the genetic diversity of the clinical isolates as determined with a panel of well-characterized, genome-spanning microsatellite markers. Our data indicate varying sensitivities of the isolates to key antimalarial candidates, both for ABS parasites and gametocyte stages. While ABS parasites were efficientlykilled, irrespective of genetic complexity, antimalarial candidates lost some gametocytocidal efficacywhen the gametocytes originated from genetically complex, multiple-clone infections. This suggests a fitnessbenefitto multiclone isolates to sustain transmission and reduce drug susceptibility. In conclusion, this is the firststudy to investigate the efficacyof antimalarial candidates on both ABS parasites and gametocytes from P. falciparum clinical isolates where the influenceof parasite genetic complexity is highlighted, ultimately aiding the malaria elimination agenda.