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

Enteroparasite and vivax malaria co-infection on the Brazil-French Guiana border: Epidemiological, haematological and immunological aspects - Fig 1

<p>(a) Frequency-specific antibody response to PvMSP-1₁₉, as determined by ELISA. The subjects were grouped into responders and non-responders to the recombinant protein. (b) Prevalence of anti-PvMSP-₁₉ IgG antibodies in the studied groups. (c) PvMSP-1₁₉ reactivity index (RI) between the studied groups as expressed in box plot format, with individual data shown as points. Multiple correlations were made using the nonparametric Kruskal-Wallis test followed by Dunn’s post hoc test (minimum to maximum values, P25%–P75% and median); significant differences were estimated using the median values for each group, and those with p < 0.05 were considered significant. ** p < 0.05, *** p = 0.001 and **** p < 0.001.</p