Authors: Michael J. Delves, Celia Miguel-Blanco, Holly Matthews, Irene Molina, Andrea Ruecker, Sabrina Yahiya, Ursula Straschil, Matthew Abraham, María Luisa León, Oliver J. Fischer, Ainoa Rueda-Zubiaurre, Jochen R. Brandt, Álvaro Cortés, Anna Barnard, Matthew J. Fuchter, Félix Calderón, Elizabeth A. Winzeler, Robert E. Sinden, Esperanza Herreros, Francisco J. Gamo, Jake Baum
Summary: Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.
Source: Nature Communications, 2018; 9 (1)