Project description:The dimorphic fungus Paracoccidioides spp. is responsible for paracoccidioidomycosis, the most prevalent systemic mycosis in Latin America, causing serious public health problems. Adequate treatment of mycotic infections is difficult, since fungi are eukaryotic organisms with a structure and metabolism similar to those of eukaryotic hosts. In this way, specific fungus targets have become important to search of new antifungal compound. The role of the glyoxylate cycle and its enzymes in microbial virulence has been reported in many fungal pathogens, including Paracoccidioides spp. Here, we show the action of argentilactone and its semi-synthetic derivative reduced argentilactone on recombinant and native isocitrate lyase from Paracoccidioides lutzii Pb01 (PbICL) in the presence of different carbon sources, acetate and glucose. Additionally, argentilactone and its semi-synthetic derivative reduced argentilactone exhibited relevant inhibitory activity against P. lutzii Pb01 yeast cells and dose-dependently influenced the transition from the mycelium to yeast phase. The other oxygenated derivatives tested, epoxy argentilactone and diol argentilactone-, did not show inhibitory action on the fungus. The results were supported by in silico experiments.
Project description:Species of the genus Paracoccidioides cause a systemic infection in human patients. Yeast cells of Paracoccidioides spp. produce melanin in the presence of L-dihydroxyphenylalanine and during infection, which may impact the pathogen survival into the host. To better understand the metabolic changes that occur in melanized Paracoccidioides spp. cells, a proteomic approach was performed to compare melanized and non-melanized Paracoccidioides brasiliensis and Paracoccidioides lutzii yeast cells. Melanization was conducted using L-dihydroxyphenylalanine as a precursor and quantitative proteomics was performed using reversed-phase chromatography coupled to high resolution mass spectrometry. When comparing melanized versus non-melanized cells, 999 and 577 differentially abundant proteins were identified for P. brasiliensis and P. lutzii, respectively. Functional enrichment and comparative analysis revealed 30 abundant biological processes in melanized P. brasiliensis and 18 in P. lutzii, while non-melanized cells from these species had 21 and 25 differentially abundant processes, respectively. Melanized cells presented abundance of other virulence-associated proteins, such as phospholipase, proteases, superoxide dismutase, heat-shock proteins, as well as proteins related to cell-wall remodeling and vesicular transport. The results suggest that L-dihydroxyphenilalanine increases virulence of Paracoccidioides spp. through a complex mechanism involving not only melanin, but other virulence factors as well.
Project description:We report the first case of fungemia caused by Paracoccidioides lutzii in a 51-year-old male farm worker from the central-west region of Brazil. The fungus was isolated from blood cultures and the species was confirmed by phylogenetic identification. Despite specific treatment and intensive care, the patient died 39 days after admission.
