Terpinen-4-ol, tyrosol, and β-lapachone as potential antifungals against dimorphic fungi

Raimunda Sâmia Nogueira Brilhante, Érica Pacheco Caetano, Rita Amanda Chaves de Lima, Francisca Jakelyne de Farias Marques, Débora de Souza Collares Maia Castelo-Branco, Charlline Vládia Silva de Melo, Glaucia Morgana de Melo Guedes, Jonathas Sales de Oliveira, Zoilo Pires de Camargo, José Luciano Bezerra Moreira, André Jalles Monteiro, Tereza de Jesus Pinheiro Gomes Bandeira, Rossana de Aguiar Cordeiro, Marcos Fábio Gadelha Rocha, José Júlio Costa Sidrim

This study aimed to evaluate the in vitro antifungal activity of terpinen-4-ol, tyrosol, and β-lapachone against strains of Coccidioides posadasii in filamentous phase (n=22) and Histoplasma capsulatum in both filamentous (n=40) and yeast phases (n=13), using the broth dilution methods as described by the Clinical and Laboratory Standards Institute, to determine the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of these compounds. The mechanisms of action of these compounds were also investigated by analyzing their effect on cell membrane permeability and ergosterol synthesis. The MIC and MFCf these compounds against C. posadasii, mycelial H. capsulatum, and yeast-like H. capsulatum, were in the following ranges: 350-5720μg/mL, 20-2860μg/mL, and 40-1420μg/mL, respectively for terpinen-4-ol; 250-4000μg/mL, 30-2000μg/mL, and 10-1000μg/mL, respectively, for tyrosol; and 0.48-7.8μg/mL, 0.25-16μg/mL, and 0.125-4μg/mL, respectively for β-lapachone. These compounds showed a decrease in MIC when the samples were subjected to osmotic stress, suggesting that the compounds acted on the fungal membrane. All the compounds were able to reduce the ergosterol content of the fungal strains. Finally, tyrosol was able to cause a leakage of intracellular molecules.