Fungal biofilms and pleomorphism under the effect of sesquiterpenes valencene and nootkatone: an in vitro and in silico approach.
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Carneiro Joara Nályda Pereira, Dos Santos Andressa Guilhermino, de Sousa Santos Elita, Dos Santos Silva Francildo, de Freitas Maria Audilene, da Silva Maria Lucilene Queiroz, Dos Santos Antonia Thassya Lucas, Fonseca Victor Juno Alencar, de Oliveira Souza Geane Gabriele, da Silva Maria Inácio, de Araújo-Neto José Bezerra, da Costa José Galberto Martins, Marinho Márcia Machado, Marinho Emmanuel Silva, de Sousa Damião Sampaio, Andrade-Pinheiro Jacqueline Cosmo, de Menezes Irwin Rose Alencar, Coutinho Henrique Douglas Melo, Arrua Juliana Moura Mendes, Morais-Braga Maria Flaviana Bezerra
Аннотация
Candida spp. and Pichia spp. undergo morphological transitions and invade host tissues through biofilm formation, making fungal infections more difficult to treat. To identify new antifungal compounds, this study evaluated the effects of valencene and nootkatone on fungal pleomorphism, biofilm eradication, interactions with virulence-associated proteins, antioxidant activity, and pharmacokinetic properties. Moist chamber assays were used to evaluate the pleomorphic transition of Candida albicans, Candida tropicalis, and Pichia kudriavzevii at concentrations ranging from 128 to 1024 μg/mL. Antioxidant activity was assessed using the DPPH (2,2-diphenyl-1-picrylhydrazyl) spectrophotometric assay. Biofilm biomass and metabolic activity were quantified by crystal violet staining and tetrazolium salt reduction, respectively. Molecular docking analyses were performed using Candida proteins retrieved from the Protein Data Bank and prepared with AutoDockTools®, while physicochemical and pharmacokinetic properties were predicted through in silico analyses. Valencene inhibited filament formation in all evaluated strains, whereas nootkatone inhibited filamentation only in C. albicans. Neither compound exhibited antioxidant activity. In biofilm assays, valencene reduced both biomass and metabolic activity in C. albicans. In C. tropicalis, both parameters were reduced by more than 50%. In P. kudriavzevii, valencene and fluconazole reduced both biofilm biomass and metabolic activity. Both compounds displayed favorable interactions with agglutinin-like sequence proteins, secreted aspartyl proteinases, Exo-1,3-β-glucanase, and Ras-like GTPase1, proteins involved in fungal adhesion and tissue invasion. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions indicated a favorable pharmacokinetic profile, including low interaction potential, efficient elimination, and high predicted skin permeability. However, further experimental studies are required to confirm their safety.