Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity

• Authors: Tatyana Almeida Tavella, Noeli Soares Melo da Silva, Natalie Spillman, Ana Carolina Andrade Vitor Kayano, Gustavo Capatti Cassiano, Adrielle Ayumi Vasconcelos, Antônio Pedro Camargo, Djane Clarys Baia da Silva, Diana Fontinha, Luis Carlos Salazar Alvarez, Letícia Tiburcio Ferreira, Kaira Cristina Peralis Tomaz, Bruno Junior Neves, Ludimila Dias Almeida, Daniel Youssef Bargieri, Marcus Vinicius Guimarães de Lacerda, Pedro Vítor Lemos Cravo, Per Sunnerhagen, Miguel Prudêncio, Carolina Horta Andrade, Stefanie Costa Pinto Lopes, Marcelo Falsarella Carazzolle, Leann Tilley, Elizabeth Bilsland, Júlio César Borges, Fabio Trindade Maranhão Costa
• Publication Year: 2021
• Journal: ACS Infectious Diseases, 7(4), pp 759 - 7769
• Link: https://doi.org/10.1021/acsinfecdis.0c00454

ABSTRACT

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.