Investigation of new targets and antifungal molecules on Candida spp. and Cryptococcus spp.

• Grant number: 21/01279-5
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2021
• End date: October 31, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Kelly Ishida
• Grantee: Kelly Ishida
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Marcio Vinicius Bertacine Dias

Abstract

Invasive fungal infections (IFIs) lead a serious health risk resulting in high rates of mortality and morbidity. Among IFIs, Candida albicans represent 50-70% of the cases, followed by Cryptococcus, Aspergillus and Pneumocystis. However, resistant and emerging fungal species have often been isolated, such as Candida auris considered a superfungus. In addition to resistance to antifungal agents, other limitations such as high toxicity, unfavorable pharmacokinetics, high cost and unavailability, further reduce the therapeutic options for fungal infections. Thus, new antifungal molecules are being researched in recent years, addressing new chemical classes and new targets in the fungal cell. Therefore, this project aims to investigate new fungal targets, such as C. auris dihydrofolate reductase (CaDHFR) and Cryptococus neoformans urease (CnURE) enzymes, and to evaluate the in vitro and in vivo antifungal activity of CaDHFR and CnURE inhibitors and synthetic molecules on Candida spp. and Cryptococcus spp. The strategies for this study will be: i) clone, express and purify the CaDHFR and CnURE enzymes; ii) crystallize and resolve the CaDHFR and CnURE structures; iii) evaluate the inhibitory effect and the molecular interaction of the inhibitors with CaDHFR and CnURE enzymes; iv) screening a library of synthetic compounds; v) select molecules with antifungal potential; vi) evaluate the fungicidal and antibiofilm effects; vii) evaluate the combination with conventional antifungals; viii) prospecting for the possible molecular target of the compounds using a library of Saccharomyces cerevisiae mutants; ix) evaluate the morphophysiological effects of the compounds; x) Analyse the toxicity of compounds on cell lines and on Galleria mellonella larval model; and finally, xi) evaluate the in vivo antifungal effect of the compounds using G. mellonella and murine infected by Candida spp. or Cryptococcus spp. (AU)

Scientific publications

(5)

(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)

DE JESUS, DANIEL FELIPE FREITAS; DE FREITAS, ALINE LUIZA DUARTE; DE OLIVEIRA, ISADORA MARIA; DE ALMEIDA, LARISSA COSTA; BASTOS, RAFAEL WESLEY; SPADARI, CRISTINA DE CASTRO; MELO, ANALY SALES DE AZEVEDO; SANTOS, DANIEL DE ASSIS; COSTA-LOTUFO, LETICIA VERAS; REIS, FLAVIA C. G.; et al. Organoselenium Has a Potent Fungicidal Effect on Cryptococcus neoformans and Inhibits the Virulence Factors. Antimicrobial Agents and Chemotherapy, v. 67, n. 3, p. 16-pg., 2023-02-23. (16/04289-3, 17/15226-5, 21/01279-5, 18/12149-2, 20/00295-4, 15/17177-6)

SANNOMIYA, MIRIAM; RODRIGUES, CLENILSON MARTINS; ARAUJO OLIVEIRA, GIOVANNA CASTRO; SOUZA CARVALHO, JULIANA CAJADO; DA COSTA, LETICIA SERAFIM; SPADARI, CRISTINA DE CASTRO; PENA FERREIRA, MARCELO JOSE; VILEGAS, WAGNER; ISHIDA, KELLY. Galloylquinic acid derivatives from Byrsonima fagifolia leaf extract and potential antifungal activity. Journal of Ethnopharmacology, v. 297, p. 7-pg., 2022-10-28. (09/52237-9, 20/16554-9, 21/01279-5)

KIRKMAN, TIM; SKETCHER, ALICE; BARROSO, VINICIUS DE MORAIS; ISHIDA, KELLY; TOSIN, MANUELA; BERTACINE DIAS, MARCIO VINICIUS. Crystal structure of dihydrofolate reductase from the emerging pathogenic fungus Candida auris. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 79, p. 11-pg., 2023-08-01. (21/01279-5, 20/03850-9, 18/11612-0)

VIANELLO, MARCO; DE JESUS, DANIEL F. F.; SAMPAIO, JORGE M.; DE OLIVEIRA, GUILHERME M.; LINCOPAN, NILTON; ISHIDA, KELLY. Possible Trichosporon asahii urinary tract infection in a critically ill COVID-19 patient. REVISTA IBEROAMERICANA DE MICOLOGIA, v. 39, n. 2, p. 3-pg., 2022-04-01. (21/01279-5)

DOS SANTOS, MURILO MOREIRA; ISHIDA, KELLY. We need to talk about Candida tropicalis: Virulence factors and survival mechanisms. Medical Mycology, v. 61, n. 8, p. 13-pg., 2023-08-02. (22/08516-5, 21/01279-5)