Background: Malaria remains a disease of devastating global impact, killing more than 800,000 people every year—the vast
majority being children under the age of 5. While effective therapies are available, if malaria is to be eradicated a broader
range of small molecule therapeutics that are able to target the liver and the transmissible sexual stages are required. These
new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance.
Methods and Findings: Little is known about the wider stage-specific activities of current antimalarials that were primarily
designed to alleviate symptoms of malaria in the blood stage. To overcome this critical gap, we developed assays to
measure activity of antimalarials against all life stages of malaria parasites, using a diverse set of human and nonhuman
parasite species, including male gamete production (exflagellation) in Plasmodium falciparum, ookinete development in P.
berghei, oocyst development in P. berghei and P. falciparum, and the liver stage of P. yoelii. We then compared 50 current
and experimental antimalarials in these assays. We show that endoperoxides such as OZ439, a stable synthetic molecule
currently in clinical phase IIa trials, are strong inhibitors of gametocyte maturation/gamete formation and impact
sporogony; lumefantrine impairs development in the vector; and NPC-1161B, a new 8-aminoquinoline, inhibits sporogony.
Conclusions: These data enable objective comparisons of the strengths and weaknesses of each chemical class at targeting
each stage of the lifecycle. Noting that the activities of many compounds lie within achievable blood concentrations, these
results offer an invaluable guide to decisions regarding which drugs to combine in the next-generation of antimalarial
drugs. This study might reveal the potential of life-cycle–wide analyses of drugs for other pathogens with complex life
cycles.