Characterization of the Gametocytocidal and Putative Transmission-Blocking Activity of Chlorotonil A Against Plasmodium falciparum

Background: Chlorotonil A, a keto-macrolide produced by the myxobacterium Sorangium cellulosum, has potent antibiotic and antimalarial activities. Notably, chlorotonil A is active against both asexual and sexual blood-stage malaria parasites, making it a promising candidate for the development of an antimalarial treatment that also reduces parasite transmission to mosquitoes. Objectives: Here, we characterize the gametocytocidal and transmission-reducing activity of chlorotonil A. Methods and results: Using direct membrane feeding assays with Plasmodium falciparum isolates from a malaria-endemic area in Gabon, we show that chlorotonil A reduces oocyst infection prevalence and intensity in Anopheles gambiae (Kisumu) mosquitoes. Furthermore, we demonstrate that chlorotonil A is a particularly fast-acting gametocytocidal compound in vitro. Fluorescence and transmission electron microscopy revealed that chlorotonil A impairs membrane integrity and induces intracellular vacuolization after 6 h of drug exposure, with accumulation of reactive oxygen species (ROS) and intracellular acidification after 24 h. Conclusions: Our findings show that chlorotonil A has the potential for development as a dual-active antimalarial.