New antimalarials targeting both the asexual and gametocyte stages

Plasmodium falciparum, the most virulent human malaria parasite, has an extended course of sexual development that is required for transmission of the disease. The 48-h asexual cycle is responsible for the clinical symptoms, while 10-12 days are required for the production of transmission-competent mature gametocytes. Mature gametocytes are resistant to all of the current antimalarial compounds, except primaquine, which is not commonly used due to the possibility of serious side effects. Consequently, even after effective treatment to clear asexual parasites, malaria transmission can continue for several weeks, prolonging the spread of the disease in the community. The inclusion of agents acting on gametocytes, as well as other exoerythrocytic parasite stages, in the drug development pipeline could facilitate the design of combination therapies that reduce morbidity and mortality at both the individual and community levels. In this article, the gametocytocidal potential of compounds currently being developed as antimalarials is reviewed and strategies are proposed for the direct screening of gametocytes and the identification of compounds that target pathways required for sexual maturation.