title: Effect of farnesol on growth, ergosterol biosynthesis, and cell permeability in Coccidioides posadasii.
abstract: Coccidioidomycosis is a systemic mycosis caused by the dimorphic fungi Coccidioides spp. The treatment for chronic and/or disseminated coccidioidomycosis can be prolonged and complicated. Therefore, the search for new drugs is necessary. Farnesol is a precursor in the sterol biosynthesis pathway that has been shown to present antifungal activity. Thus, the objective of this study was to evaluate the in vitro antifungal activity of farnesol alone and in combination with antifungal agents against clinical and environmental strains of Coccidioides posadasii as well as to determine their effect on the synthesis of ergosterol and on cell permeability. This study employed the broth macrodilution method to determine the MIC of farnesol against 18 strains of C. posadasii. Quantification of ergosterol was performed with 10 strains of C. posadasii after exposure to subinhibitory concentrations of farnesol. Finally, the activity of farnesol was evaluated in the presence of osmotic stress, induced by the addition of NaCl to the culture medium, during the susceptibility tests. The results showed that farnesol exhibited low MICs (ranging from 0.00171 to 0.01369 mg/liter) against all tested strains. The combination of farnesol with the antifungals showed synergistic effects (fractional inhibitory concentration index [FICI] ≤ 0.5). As for the ergosterol quantification, it was observed that exposure to subinhibitory concentrations of farnesol decreased the amount of ergosterol extracted from the fungal cells. Furthermore, farnesol also showed lower MIC values when the strains were subjected to osmotic stress, indicating the action of this compound on the fungal membrane. Thus, due to the high in vitro antifungal activity, this work brings perspectives for the performance of in vivo studies to further elucidate the effects of farnesol on the host cells.
authors: Department of Pathology and Legal Medicine, College of Medicine, Post-Graduation Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: Raimunda Sâmia Nogueira
authors: RS
authors: Brilhante
authors: Rita Amanda Chaves
authors: RA
authors: de Lima
authors: Erica Pacheco
authors: EP
authors: Caetano
authors: João Jaime Giffoni
authors: JJ
authors: Leite
authors: Débora de Souza Collares Maia
authors: Dde S
authors: Castelo-Branco
authors: Joyce Fonteles
authors: JF
authors: Ribeiro
authors: Tereza de Jesus Pinheiro Gomes
authors: Tde J
authors: Bandeira
authors: Rossana de Aguiar
authors: Rde A
authors: Cordeiro
authors: André Jalles
authors: AJ
authors: Monteiro
authors: José Júlio Costa
authors: JJ
authors: Sidrim
authors: Marcos Fábio Gadelha
authors: MF
authors: Rocha
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003045:Coccidioides / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004875:Ergosterol / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005204:Farnesol / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009994:Osmolar Concentration; D009997:Osmotic Pressure; D012965:Sodium Chloride / Q000737:chemistry
chemical_list: D000935:Antifungal Agents; D012965:Sodium Chloride; D005204:Farnesol; D015725:Fluconazole; D004875:Ergosterol