Inhibition of Paracoccidioides lutzii Pb01 isocitrate lyase by the natural compound argentilactone and its semi-synthetic derivatives

• Published in: PloS one 2014-04, Vol.9 (4), p.e94832-e94832
• Main Authors: Prado, Renata Silva do, Alves, Ricardo Justino, Oliveira, Cecília Maria Alves de, Kato, Lucília, Silva, Roosevelt Alves da, Quintino, Guilherme Oliveira, do Desterro Cunha, Silvio, de Almeida Soares, Célia Maria, Pereira, Maristela
• Format: Article
• Language: English
• Subjects: Acetic acid; Antifungal agents; Binding Sites; Biology and Life Sciences; Candida albicans; Carbon; Carbon sources; Derivatives; Drug therapy; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Fungi; Fungicides; Glyoxylate cycle; Health aspects; Health problems; Isocitrate lyase; Isocitrate Lyase - antagonists & inhibitors; Isocitrate Lyase - chemistry; Isocitrate Lyase - metabolism; Laboratories; Lactones - chemistry; Lactones - pharmacology; Ligands; Medicine and Health Sciences; Metabolism; Microorganisms; Molecular Docking Simulation; Molecular Dynamics Simulation; Mycelium - cytology; Mycelium - drug effects; Mycoses; Mycosis; Paracoccidioides; Paracoccidioides - drug effects; Paracoccidioides - enzymology; Paracoccidioides - growth & development; Paracoccidioides lutzii; Physical Sciences; Proteins; Public health; Solvents - chemistry; South American blastomycosis; Structural Homology, Protein; Thermodynamics; Virulence; Yeast
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094832

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.