Identification of molecular targets in Cryptococcus neoformans and the importance of AAP1 amino acid permease for virulence factors

• Grant number: 16/23890-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2017
• End date: April 30, 2018
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Marcelo Afonso Vallim
• Grantee: João Miguel Alves Nunes
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil

Abstract

The opportunistic fungus Cryptococcus neoformans is of great medical importance, it can be founf in the most diverse environments, both rural and urban, and it affects serious problems in immunocompromised patients such as cryptococcal meningitis that is highly lethal if not treated. The search for drugs against eukaryotic pathogens is difficult, since there have low selective toxicity, restricting the options of antifungal drugs, making treatment difficult. Due to these reasons, we decided to search for molecular targets unique to C. neoformans, therefore resulting in a high selective toxicity. The acquisition, synthesis and recycling of nutrients by the cell have been identified as divergent between the upper and lower eukaryotes. Preliminary data obtained by the LIMIC-UNIFESP Cryptococcus group demonstrate that elements linked to biosynthesis (enzymes) and amino acid uptake (permeases) are potent inhibitors of fungal growth. Previous studies have shown that the biosynthesis pathways of threonine and tryptophan are essential for the fungus and the permeases AAP4 and AAP5 are intrinsically related to virulence. Also, we shown that an effective fungicidal action for sakuranetin compound, isolated and purified from Baccharis retusa by the Biorganic group (LABIORG) from UNIFESP Diadema, however its molecucar target remains unknown. Therefore, this project aims are: I) address the importance of permease (AAP1) for the virulence factors in C. neoformans and II) identify the sakuranetin molecular target employing techniques that generated random C. neoformans mutants inactivating its target resulting in a resistant strain. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CALVETE, CRISLAINE LAMBIASE; MARTHO, KEVIN FELIPE; FELIZARDO, GABRIELLE; PAES, ALEXANDRE; NUNES, JOAO MIGUEL; FERREIRA, CAMILA OLIVEIRA; VALLIM, MARCELO A.; PASCON, RENATA C.. Amino acid permeases in Cryptococcus neoformans are required for high temperature growth and virulence; and are regulated by Ras signaling. PLoS One, v. 14, n. 1, JAN 25 2019. (16/14542-8, 16/23890-0, 15/04400-9)