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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Antifungal Activity, Toxicity, and Membranolytic Action of a Mastoparan Analog Peptide

Texto completo
Autor(es):
Singulani, Junya de Lacorte [1] ; Galeane, Mariana Cristina [1] ; Ramos, Marina Dorisse [1] ; Gomes, Paulo Cesar [1] ; dos Santos, Claudia Tavares [1] ; de Souza, Bibiana Monson [2] ; Palma, Mario Sergio [2] ; Fusco Almeida, Ana Marisa [1] ; Soares Mendes Giannini, Maria Jose [1]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Sao Paulo State Univ, UNESP, Dept Clin Anal, Sch Pharmaceut Sci, Araraquara, SP - Brazil
[2] Sao Paulo State Univ, UNESP, Inst Biosci, Dept Biol, Ctr Study Social Insects, Rio Claro - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY; v. 9, DEC 6 2019.
Citações Web of Science: 0
Resumo

Invasive fungal infections, such as cryptococcosis and paracoccidioidomycosis are associated with significant rates of morbidity and mortality. Cryptococcosis, caused by Cryptococcus neoformans, is distributed worldwide and has received much attention as a common complication in patients with HIV. Invasive fungal infections are usually treated with a combination of amphotericin B and azoles. In addition, 5-fluorocytosine (5-FC) is applied in cryptococcosis, specifically to treat central nervous system infection. However, host toxicity, high cost, emerging number of resistant strains, and difficulty in developing new selective antifungals pose challenges. The need for new antifungals has therefore prompted a screen for inhibitory peptides, which have multiple mechanisms of action. The honeycomb moth Galleria mellonella has been widely used as a model system for evaluating efficacy of antifungal agents. In this study, a peptide analog from the mastoparan class of wasps (MK58911) was tested against Cryptococcus spp. and Paracoccidioides spp. In addition, peptide toxicity tests on lung fibroblasts (MRC5) and glioblastoma cells (U87) were performed. Subsequent tests related to drug interaction and mechanism of action were also performed, and efficacy and toxicity of the peptide were evaluated in vivo using the G. mellonella model. Our results reveal promising activity of the peptide, with an MIC in the range of 7.8-31.2 mu g/mL, and low toxicity in MRC and U87 cells (IC50 > 500 mu g/mL). Taken together, these results demonstrate that MK58911 is highly toxic in fungal cells, but not mammalian cells (SI > 16). The mechanism of toxicity involved disruption of the plasma membrane, leading to death of the fungus mainly by necrosis. In addition, no interaction with the drugs amphotericin B and fluconazole was found either in vitro or in vivo. Finally, the peptide showed no toxic effects on G. mellonella, and significantly enhanced survival rates of larvae infected with C. neoformans. Although not statistically significant, treatment of larvae with all doses of MK58911 showed a similar trend in decreasing the fungal burden of larvae. These effects were independent of any immunomodulatory activity. Overall, these results present a peptide with potential for use as a new antifungal drug to treat systemic mycoses. (AU)

Processo FAPESP: 16/16212-5 - Proteopeptídeos naturais da fauna, flora e microbiota brasileira como potenciais modelos para o desenvolvimento racional de novos fármacos de uso terapêutico: isolamento, elucidação estrutural, síntese química e ensaios de atividade funcional
Beneficiário:Mario Sergio Palma
Linha de fomento: Auxílio à Pesquisa - Programa BIOTA - Temático
Processo FAPESP: 17/06658-9 - Plataforma para desenvolvimento de antifúngicos em sistema nanoestruturado lipídico visando eficácia e segurança em modelos animais alternativos
Beneficiário:Junya de Lacorte Singulani
Linha de fomento: Bolsas no Brasil - Pós-Doutorado