Evaluation of violacein antimalarial effect on Plasmodium vivax and P. falciparum isolates from Brazilian Amazon and analysis of violacein activity on P. chabaudi multi-drug resistant infected mice

Abstract

Malaria is responsible for about 300 million infections and 1 million deaths per year. In Brazil, in 2009, there were approximately 300,000 cases, in which vivax infections were responsible for about 85% of reported cases. Moreover, in the past 10 years, it has been observed an augmentation in complications resulting in an increase in hospital admissions in Brazil and the world. Indeed, it has been frequently reported treatment failure of Plasmodium falciparum, mainly, and P. vivax by using conventional antimalarials (e.g. chloroquine and quinine). Thus, artemisinin (or its derivatives) combination therapies (ACT) are currently recommended, as this compound is the solely molecule in which parasite did not develop resistance yet. In P. falciparum, this resistance is also associated with a highly expression and mutations in a molecule named multi-drug resistance transporter 1 (MDR1), encoded by the MDR1 gene. Nevertheless, in P. vivax mutations in this molecule are not predictive of resistance, despite been reported it. In recent years, it has been shown that strains of P. chabaudi, a rodent parasite, selected for resistance to the treatment with artesunate (artemisinin derivate) and/or mefloquine express high levels of MDR1. In parallel, we have recently demonstrated that violacein; a purple pigment produced by the bacterium Chromobacterium violaceum, was able to inhibit the development of P. falciparum laboratory-adapted strains, and was capable to control the parasitemia of P. chabaudi-infected animals. Therefore, we intend to evaluate the antimalarial activity of violacein in P. falciparum Amazonian fresh isolates, and P. vivax immediately after harvesting from infected patients (ex vivo assays). We will also intend to analyze the effect of violacein on parasitemia of mice infected with resistant strains of P. chabaudi, and determine the expression levels of mdr1 gene and protein (MDR1).