Farnesol inhibits in vitro growth of the Cryptococcus neoformans species complex with no significant changes in virulence-related exoenzymes

Abstract

Farnesol is a sesquiterpene alcohol that modulates cell-to-cell communication in Candida albicans. In recent years, several studies have shown that this molecule presents inhibitory effects against non-albicans Candida species, Paracoccidioides brasiliensis and bacteria. The present study aimed at determining the effect of farnesol on the growth of strains of the Cryptococcus neoformans species complex, through microdilution assays. In addition, the effect of farnesol on the synthesis of phospholipase and protease - important virulence-associated enzymes - by C. neoformans and Cryptococcus gattii was also investigated. A total of 36 strains were studied, out of which 20 were from veterinary sources, 8 were from human cases and 8 were from a reference collection. The minimum inhibitory concentrations (MICs) were determined in accordance with the M27-A3 protocol as described by the CLSI and farnesol was tested at a concentration range of 0.29-150 μM. Phospholipase and protease activities were evaluated through growth on egg yolk agar and spectrophotometry, respectively, after pre-incubating the strains at different farnesol concentrations (MIC/4, MIC/2 and MIC). It was observed that farnesol presents an inhibitory activity against C. neoformans and C. gattii (MIC range: 0.29-75.0 μM). Although farnesol did not significantly alter phospholipase activity, a tendency to decrease this activity was observed. Concerning protease, no statistically significant differences were observed when comparing the production before and after pre-incubation at different farnesol concentrations. Based on these findings, it can be concluded that farnesol has in vitro inhibitory activity against C. neoformans and C. gattii, but has little impact on the production of the analyzed virulence factors.

Effect of Farnesol on Growth, Ergosterol Biosynthesis, and Cell Permeability in Coccidioides posadasii

“…Derengowski et al demonstrated the in vitro activity of farnesol against the dimorphic fungus Paracoccidioides brasiliensis, which presented an average MIC of 25 M (16). Moreover, recent studies from our group performed with the species Cryptococcus neoformans and C. gattii showed MIC values ranging from 0.29 to 75 M for both species (17), while the farnesol MICs ranged from 9.37 to 150 M against different Candida species (18).…”

“…More recently, many studies have described the activity of farnesol against different species of fungi (15)(16)(17)(18). In this study, for the first time, the antifungal activity of farnesol against the primary pathogen C. posadasii, the causative agent of coccidioidomycosis, was investigated.…”

“…The results obtained were visually read after 48 h of incubation at 35°C. The MICs for farnesol (17), itraconazole, voriconazole, and caspofungin alone or in combination were defined as the lowest concentration of drug capable of inhibiting 80% of fungal growth, when compared to the drug-free control tube (23). As for amphotericin B alone, the MIC was the lowest concentration at which no fungal growth was observed.…”

Cryptococcus neoformanscan form titan-like cellsin vitroin response to multiple signals that require the activation of several transduction pathways

“…In C. albicans , farnesol represses the transition from yeast to hyphae [69]. In C. neoformans , this molecule inhibits growth in vitro and has an effect on the secretion of phospholipases and proteases [70]. Previous reports demonstrate that QS regulates the formation of biofilms, the release of the capsular polysaccharide glucuronoxylomannan (GXM) and the melanin synthesis of this pathogen [30].…”

Caracterização funcional do gene codificador de uma proteína com peptídeo sinal, masA, de Aspergillus fumigatus

“…Além disso, farnesol é capaz de inibir a formação de biofilme de C. albicans de uma maneira tempo-dependente, onde a inibição ocorre preferencialmente nos momentos iniciais da formação do biofilme (Ramage et al, 2002) o qual é uma possível explicação da não influência do farnesol em células já na fase micelial de desenvolvimento (Mosel et al, 2005). Várias espécies fúngicas são afetadas pelo farnesol como a inibição da morfogênese do fungo patogênico dimórfico Paracoccidioides brasiliensis (Derengowski et al, 2009) e a alteração do crescimento de Cryptococcus neoformans (Cordeiro et al, 2012) e Penicillium expansum (Liu et al, 2009). Para o fungo leveduriforme Saccharomyces cerevisiae, o farnesol exibe um efeito inibitório no crescimento, causado pela geração mitocondrial de espécies EROs (Machida et al, 1998).…”