Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity

Antimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known its biological activity against cancer cells several pathogens, including parasite, Plasmodium falciparum (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis. Mechanistically, binds Pf chaperones, PfHsp90 PfHsp70-1, compromising latter’s ATPase chaperone activities. Additionally, violacein-treated parasites exhibited increased unfolding proteasomal degradation. The uncoupling parasite stress response reflects multistage growth inhibitory effect promoted by violacein. Despite evidence proteotoxic stress, did not inhibit global synthesis via UPR activation—a process highly dependent on in agreement notion violacein-induced proteostasis collapse. Our data highlight importance functioning chaperone–proteasome system development differentiation. Thus, violacein-like small molecule might provide good scaffold probe examining molecular network and/or antiplasmodial drug design.