Decyl Gallate as a Possible Inhibitor of N-Glycosylation Process in Paracoccidioides lutzii

Autor(es):Mostrar menos -

Alves de Paula e Silva, Ana Carolina ^[1] ; de Oliveira, Haroldo Cesar ^[1] ; Scorzoni, Liliana ^[1] ; Marcos, Caroline Maria ^[1] ; dos Santos, Claudia Tavares ^[1] ; Fusco-Almeida, Ana Marisa ^[1] ; Guerta Salina, Ana Carolina ^{[2, 3]} ; Medeiros, Alexandra Ivo ^[3] ; Almeida, Fausto ^[4] ; Li, Sheena Claire ^{[5, 6]} ; Boone, Charles ^[5] ; Mendes-Giannini, Maria J. S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Paulista, Fac Ciencias Farmaceut, Dept Clin Anal, Araraquara, SP - Brazil

^[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biochem & Immunol, Ribeirao Preto, SP - Brazil

^[3] Univ Estadual Paulista, Fac Ciencias Farmaceut, Dept Biol Sci, Araraquara, SP - Brazil

^[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Cellular Mol Biol & Pathogen Bioagents, Ribeirao Preto, SP - Brazil

^[5] Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Dept Mol Genet, Toronto, ON - Canada

^[6] RIKEN Ctr Sustainable Resource Sci, Saitama - Japan

• Tipo de documento: Artigo Científico
• Fonte: Antimicrobial Agents and Chemotherapy; v. 63, n. 11 NOV 2019.
• Citações Web of Science: 0

Resumo

The available antifungal therapeutic arsenal is limited. The search for alternative drugs with fewer side effects and new targets remains a major challenge. Decyl gallate (G14) is a derivative of gallic acid with a range of biological activities and broad-spectrum antifungal activity. Previously, our group demonstrated the promising anti-Paracoccidioides activity of G14. In this work, to evaluate the antifungal characteristics of G14 for Paracoccidioides lutzii, a chemical-genetic interaction analysis was conducted on a Saccharomyces cerevisiae model. N-glycosylation and/or the unfolded protein response pathway was identified as a high-confidence process for drug target prediction. The overactivation of unfolded protein response (UPR) signaling was confirmed using this model with IRE1/ATF6/PERK genes tagged with green fluorescent protein (GFP). In P. lutzii, this prediction was confirmed by the low activity of glycosylated enzymes {[}alpha-(1,3)-glucanase, N-acetyl-alpha-D-glucosaminidase (NAGase), and alpha-(1,4)-amylase], by hyperexpression of genes involved with the UPR and glycosylated enzymes, and by the reduction in the amounts of glycosylated proteins and chitin. All of these components are involved in fungal cell wall integrity and are dependent on the N-glycosylation process. This loss of integrity was confirmed by the reduction in mitochondrial activity, impaired budding, enhancement of wall permeability, and a decrease in viability. These events led to a reduction of the ability of fungi to adhere on human lung epithelial cells (A549) in vitro. Therefore, G14 may have an important role in balancing the inflammatory reaction caused by fungal infection, without interfering with the microbicidal activity of nitric oxide. This work provides new information on the activity of G14, a potential anti-Paracoccidioides compound. (AU)

• Processo FAPESP: 16/17048-4 - Sistema de dois componentes de transdução de sinais (TCST) como novo alvo para o delineamento de peptídeos antifúngicos
• Beneficiário: Caroline Maria Marcos
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/14023-8 - Uso de peptídeos com atividade anti-adesiva em Paracoccidoides spp. na terapêutica e profilaxia da paracoccidioidomicose
• Beneficiário: Haroldo Cesar de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/03700-9 - Animais alternativos aplicados à interação Paracoccidioides-hospedeiro para o desenvolvimento de estudos de virulência, eficácia e toxicidade de compostos antifúngicos e tratamentos preventivos
• Beneficiário: Maria José Soares Mendes Giannini
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/10917-9 - Modelos animais alternativos: Virulência de diferentes espécies filogenéticas de Paracoccidioides e efeito das proteínas 43kDa e 30kDa e de seus anticorpos
• Beneficiário: Liliana Scorzoni
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado