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

Autor: Mario Sergio Palma, Bibiana Monson de Souza, Claudia Tavares dos Santos, Junya de Lacorte Singulani, Marina Dorisse Ramos, Maria José Soares Mendes Giannini, Mariana Cristina Galeane, Ana Marisa Fusco Almeida, Paulo César Gomes
Přispěvatelé: Universidade Estadual Paulista (Unesp)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Scopus
Repositório Institucional da UNESP
Universidade Estadual Paulista (UNESP)
instacron:UNESP
Frontiers in Cellular and Infection Microbiology, Vol 9 (2019)
Frontiers in Cellular and Infection Microbiology
Popis: Made available in DSpace on 2020-12-12T01:51:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-12-06 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 μg/mL, and low toxicity in MRC and U87 cells (IC50 > 500 μg/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. Department of Clinical Analysis School of Pharmaceutical Sciences São Paulo State University-UNESP Department of Biology Center for the Study of Social Insects Institute of Biosciences São Paulo State University-UNESP Department of Clinical Analysis School of Pharmaceutical Sciences São Paulo State University-UNESP Department of Biology Center for the Study of Social Insects Institute of Biosciences São Paulo State University-UNESP
Databáze: OpenAIRE
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