Limitation of pantothenate bioavailability in Anopheles stephensi by second-generation pantazines enhances restriction of Plasmodium development

Abstract

Plasmodium parasites require pantothenate (Pan) from their hosts to synthesize coenzyme A (CoA), an essential metabolic cofactor. While blood-stage parasites can utilize both Pan and the immediate CoA precursor phosphopantetheine from mammals to synthesize CoA, mosquito-stage parasites rely critically on insect-derived Pan to synthesize CoA. Mosquito host pantothenate kinase (PanK), the rate-limiting enzyme in CoA biosynthesis, is therefore a promising drug target to reduce Pan bioavailability for parasite development. In support, we previously showed that the mammalian PanK activator PZ-2891 restricts Plasmodium yoelii and Plasmodium falciparum development in Anopheles stephensi . Two second-generation pantazines, PZ-3022 and PZ-3883, with improved stability significantly reduced Pan levels in A. stephensi at different time points post-treatment and had no effect on P. falciparum growth in vitro. In infection assays, mosquitoes provisioned with these pantazines exhibited markedly decreased midgut oocyst and salivary gland sporozoite burdens for both parasite species. These findings confirm that pantazines can effectively impair mosquito-stage parasite development and represent promising transmission-blocking small molecules.