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 efficacy and to confirm that 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 efficacy of compounds with multistage activity. Here, we evaluated the efficacy
of 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 efficacy to 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 efficiently killed, irrespective
of genetic complexity, antimalarial candidates lost some gametocytocidal efficacy when
the gametocytes originated from genetically complex, multiple-clone infections. This
suggests a fitness benefit to multiclone isolates to sustain transmission and reduce drug
susceptibility. In conclusion, this is the first study to investigate the efficacy of antimalarial candidates on both ABS parasites and gametocytes from P. falciparum clinical isolates
where the influence of parasite genetic complexity is highlighted, ultimately aiding the
malaria elimination agenda
