Identification of the mechanism of action of violacein and intermediates against Plasmodium spp

Abstract

Parasites of the genus Plasmodium (causative agent of Malaria) are responsible for over half a million deaths a year; and this problem could be compounded by the increasing resistance of these parasites to commonly used drugs. The development of new antimalarial drugs is therefore of vital importance. Violacein is a violet indocarbazole pigment naturally produced by bacteria of the genus Chromobacterium, which are commonly found in water and soil of tropical regions of the world. Violacein has antiparasitic activities and the potential of inducing apoptosis in certain cancer cells. Violacein kills resistant Plasmodium falciparum strains in vitro and controls malaria in mice. These characteristics indicate the potential of Violacein in biochemical research and in the development for clinical use. However, the mode of action of this compound remains unknown, thus, identification of the targets of Violacein and could contribute to the development this molecule's potential as a therapeutic agent. The large-scale production of Violacein has thus far not been efficient, restricting the use of Violacein. Here we propose to optimize the synthesis and purification of violacein and intermediate compounds (through the use of a synthetic violacein operon), and assess the antiplasmodial activity of these products. Furthermore, we plan to verify the mode of action of violacein suggested by chemical genomic profiling, prepare a manuscript combining results obtained and Cambridge and at UNICAMP, and draft a proposal for joint funding towards the development of a violacein based therapy. (AU)