Two-component signal transduction (TCST) system as a new target for the treatment of paracoccidioidomycosis

• Grant number: 16/17048-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2016
• End date: January 31, 2021
• Field of knowledge: Health Sciences - Pharmacy
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Maria José Soares Mendes Giannini
• Grantee: Caroline Maria Marcos
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated scholarship(s): 19/09545-6 - Yeast protein phosphatase Ptc1 in the regulation of the cell cycle S-phase, BE.EP.PD

Abstract

Several fungal species are able to causing serious diseases to humans, and some are fatal when untreated, among these diseases are: aspergillosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis and paracoccidioidomycosis (PCM), and these currently represent a threat to global health. For PCM, a systemic mycosis of great interest in Latin America and Brazil, there is a very limited antifungal arsenal and being that most agents have high toxicity. The incidence of fungal infections has increased over the past three decades and at the same time we have increased resistance to antifungal drugs without new advances in in relation to therapy. Even with the extensive search for the development of new therapeutic strategies today a still very limited number of drugs are available to treat not only the PCM, but also other systemic mycoses. The ideal target for the development of new antifungal agents must fulfill some requirements such as be present in the most pathogenic fungi and be involved in the pathogenicity and / or vitality and preferably be absent in human in order to cause the least toxicity to the host. An interesting target for such purpose can be, for example, a signal transduction pathway conserved across most fungi and active in regulating the expression of virulence factors, such as the two component system (TCST), consisting of a histidine kinase sensor and a response regulator which can act as a transcription factor, which is the dominant mechanism by which most pathogens responds to external stimuli that lead to activation of histidine kinase by autophosphorylation. Thus the TCST system plays an important role in regulating gene expression including genes related to virulence, dimorphism, biofilm formation, antimicrobial resistance among others, and also is not present in mammalian cells, therefore represents an attractive target for therapy. Thus, this study aims to evaluate the TCST system as a new target for development of new antifungal and identification of peptide inhibitors of this system. (AU)

Scientific publications

(12)

(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)

SCORZONI, LILIANA; DE PAULA E SILVA, ANA C. A.; MARCOS, CAROLINE M.; ASSATO, PATRICIA A.; DE MELO, WANESSA C. M. A.; DE OLIVEIRA, HAROLDO C.; COSTA-ORLANDI, CAROLINE B.; MENDES-GIANNINI, MARIA J. S.; FUSCO-ALMEIDA, ANA M.. Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis. FRONTIERS IN MICROBIOLOGY, v. 8, JAN 23 2017. (15/03700-9, 13/10917-9, 16/17048-4, 15/14023-8)

SINGULANI, JUNYA L.; SCORZONI, LILIANA; DE OLIVEIRA, HAROLDO C.; MARCOS, CAROLINE M.; ASSATO, PATRICIA A.; FUSCO-ALMEIDA, ANA MARISA; MENDES-GIANNINI, MARIA JOSE S.. Applications of Invertebrate Animal Models to Dimorphic Fungal Infections. JOURNAL OF FUNGI, v. 4, n. 4, DEC 2018. (17/06658-9, 16/17048-4, 15/14023-8)

MARCOS, CAROLINE MARIA; DE OLIVEIRA, HAROLDO CESAR; ASSATO, PATRICIA AKEMI; DE ANDRADE, CLEVERTON ROBERTO; FUSCO-ALMEIDA, ANA MARISA; SOARES MENDES-GIANNINI, MARIA JOSE. Paracoccidioides brasiliensis 14-3-3 protein is important for virulence in a murine model. Medical Mycology, v. 57, n. 7, p. 900-904, OCT 2019. (16/17048-4, 15/14023-8, 15/03700-9)

MARCOS, CAROLINE MARIA; TAMER, GABRIELLE; DE OLIVEIRA, HAROLDO CESAR; ASSATO, PATRICIA AKEMI; SCORZONI, LILIANA; SANTOS, CLAUDIA TAVARES; SINGULANI, JUNYA DE LACORTE; DA SILVA, JULHIANY DE FATIMA; DE ALMEIDA, RODRIGO; ALVES DE PAULA E SILVA, ANA CAROLINA; et al. Down-regulation of TUFM impairs host cell interaction and virulence by Paracoccidioides brasiliensis. SCIENTIFIC REPORTS, v. 9, NOV 20 2019. (13/10917-9, 16/17048-4, 15/14023-8, 15/03700-9, 14/10446-9)

ALVES DE PAULA E SILVA, ANA CAROLINA; DE OLIVEIRA, HAROLDO CESAR; SCORZONI, LILIANA; MARCOS, CAROLINE MARIA; DOS SANTOS, CLAUDIA TAVARES; FUSCO-ALMEIDA, ANA MARISA; GUERTA SALINA, ANA CAROLINA; MEDEIROS, ALEXANDRA IVO; ALMEIDA, FAUSTO; LI, SHEENA CLAIRE; et al. Decyl Gallate as a Possible Inhibitor of N-Glycosylation Process in Paracoccidioides lutzii. Antimicrobial Agents and Chemotherapy, v. 63, n. 11, NOV 2019. (16/17048-4, 15/14023-8, 15/03700-9, 13/10917-9)

ZANCANELA, DANIELA CERVELLE; FUNARI, CRISTIANO SOLEO; HERCULANO, RONDINELLI DONIZETTI; MELLO, VINICIUS MOREIRA; RODRIGUES, CLENILSON MARTINS; BORGES, FELIPE AZEVEDO; DE BARROS, NATAN ROBERTO; MARCOS, CAROLINE MARIA; FUSCO ALMEIDA, ANA MARISA; GUASTALDI, ANTONIO CARLOS. Natural rubber latex membranes incorporated with three different types of propolis: Physical-chemistry and antimicrobial behaviours. Materials Science & Engineering C-Materials for Biological Applications, v. 97, p. 576-582, APR 2019. (15/11759-3, 17/19603-8, 14/17526-8, 16/17048-4)

MARCOS, CAROLINE MARIA; DE OLIVEIRA, HAROLDO CESAR; ASSATO, PATRICIA AKEMI; CASTELLI, RAFAEL FERNANDO; FUSCO-ALMEIDA, ANA MARISA; MENDES-GIANNINI, MARIA JOSE SOARES. Drk1, a Dimorphism Histidine Kinase, Contributes to Morphology, Virulence, and Stress Adaptation in Paracoccidioides brasiliensis. JOURNAL OF FUNGI, v. 7, n. 10, OCT 2021. (16/17048-4, 15/14023-8, 15/03700-9)

SCORZONI, LILIANA; ALVES DE PAULA E SILVA, ANA CAROLINA; DE OLIVEIRA, HAROLDO CESAR; MARCOS, CAROLINE MARIA; SINGULANI, JUNYA DE LACORTE; FUSCO-ALMEIDA, ANA MARISA; SOARES MENDES-GIANNINI, MARIA JOSE. Can passage in Galleria mellonella activate virulence factors of Paracoccidioides brasiliensis as in the murine model?. Medical Mycology, v. 56, n. 3, p. 374-377, APR 2018. (15/14023-8, 14/10446-9, 15/03700-9, 16/17048-4, 13/10917-9)

FREGONEZI, NATHALIA FERREIRA; OLIVEIRA, LARIANE TEODORO; SINGULANI, JUNYA DE LACORTE; MARCOS, CAROLINE MARIA; DOS SANTOS, CLAUDIA TAVARES; TAYLOR, MARIA LUCIA; MENDES-GIANNINI, MARIA JOSE SOARES; DE OLIVEIRA, HAROLDO CESAR; FUSCO-ALMEIDA, ANA MARISA. Heat Shock Protein 60, Insights to Its Importance in Histoplasma capsulatum: From Biofilm Formation to Host-Interaction. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 10, JAN 22 2021. (18/15877-9, 15/14023-8, 16/11836-0, 17/06658-9, 16/17048-4)

SCORZONI, LILIANA; ALVES DE PAULA E SILVA, ANA CAROLINA; DE OLIVEIRA, HAROLDO CESAR; DOS SANTOS, CLAUDIA TAVARES; SINGULANI, JUNYA DE LACORTE; ASSATO, PATRICIA AKEMI; MARCOS, CAROLINE MARIA; OLIVEIRA, LARIANE TEODORO; FREGONEZI, NATHALIA FERREIRA; PEREIRA ROSSI, DIEGO CONRADO; et al. In Vitro and In Vivo Effect of Peptides Derived from 14-3-3 Paracoccidioides spp. Protein. JOURNAL OF FUNGI, v. 7, n. 1, JAN 2021. (16/08730-6, 16/17048-4, 15/14023-8, 15/03700-9, 13/10917-9, 14/10446-9)

DE OLIVEIRA, HAROLDO C.; MICHALOSKI, JUSSARA S.; DA SILVA, JULHIANY F.; SCORZONI, LILIANA; DE PAULA E SILVA, ANA C. A.; MARCOS, CAROLINE M.; ASSATO, PATRICIA A.; YAMAZAKI, DANIELLE S.; FUSCO-ALMEIDA, ANA M.; GIORDANO, RICARDO J.; et al. Peptides Derived from a Phage Display Library Inhibit Adhesion and Protect the Host against Infection by Paracoccidioides brasiliensis and Paracoccidioides lutzii. FRONTIERS IN PHARMACOLOGY, v. 7, DEC 23 2016. (08/54806-8, 15/14023-8, 15/03700-9, 16/17048-4, 13/10917-9)

BERNARDI, THAIS; DA SILVA, JULHIANY DE FATIMA; VICENTIN, JULIANA; DE OLIVEIRA, HAROLDO CESAR; ASSATO, PATRICIA AKEMI; MARCOS, CAROLINE MARIA; ALVES DE PAULA E SILVA, ANA CAROLINA; MORAES DA SILVA, ROSANGELA APARECIDA; REGASINI, LUIS OCTAVIO; SIQUEIRA SILVA, DULCE HELENA; et al. Anti-apoptotic effects of decyl gallate on the induction of apoptosis in A549 pneumocytes by Paracoccidioides brasiliensis gp43. Medical Mycology, v. 55, n. 8, p. 890-894, NOV 2017. (11/18038-9, 15/14023-8, 16/17048-4)