Antifungal activity of linalool against fluconazole-resistant clinical strains of vulvovaginal Candida albicans and its predictive mechanism of action

Abstract

Candida albicans is the most frequently isolated opportunistic pathogen in the female genital tract, with 92.3% of cases in Brazil associated with vulvovaginal candidiasis (VVC). Linalool is a monoterpene compound from plants of the genera Cinnamomum , Coriandrum, Lavandula , and Citrus that has demonstrated a fungicidal effect on strains of Candida spp., but its mechanism of action is still unknown. For this purpose, broth microdilution techniques were applied, as well as molecular docking in a predictive manner for this mechanism. The main results of this study indicated that the C. albicans strains analyzed were resistant to fluconazole and sensitive to linalool at a dose of 256 µg/mL. Furthermore, the increase in the minimum inhibitory concentration (MIC) of linalool in the presence of sorbitol and ergosterol indicated that this molecule possibly affects the cell wall and plasma membrane integrity of C. albicans . Molecular docking of linalool with proteins that are key in the biosynthesis and maintenance of the cell wall and the fungal plasma membrane integrity demonstrated the possibility of linalool interacting with three important enzymes: 1,3-β-glucan synthase, lanosterol 14α-demethylase, and Δ 14-sterol reductase. In silico analysis showed that this monoterpene has theoretical but significant oral bioavailability, low toxic potential, and high similarity to pharmaceuticals. Therefore, the findings of this study indicated that linalool probably causes damage to the cell wall and plasma membrane of C. albicans , possibly by interaction with important enzymes involved in the biosynthesis of these fungal structures, in addition to presenting low in silico toxic potential.

The Volatile Organic Compounds of Streptomyces spp.: An In-Depth Analysis of Their Antifungal Properties

“…Linalool oxide : This is a monoterpene acyclic tertiary alcohol that has been described as having antifungal activity against the fungus plant pathogen Guignardia camelliae [ 65 ], Candida albicans [ 66 ], and Trichophyton rubrum [ 67 ]. It has a lot of applications as a vitamin E precursor, in cosmetics, and in detergents, being the most widely used terpene in the food industry because of its fragrant and flavor properties [ 68 ].…”

Lavandula angustifolia Essential Oils as Effective Enhancers of Fluconazole Antifungal Activity against Candida albicans

“…Recent studies of antifungal activity of linalool against the resistant strains of C. albicans have shown good correlation between experimental and theoretical studies performed by molecular docking. It was found that linalool probably causes damage of the C. albicans cell wall and plasma membrane, what can be explained by its interaction with three important enzymes involved in their biosynthesis, including lanosterol 14-α-demethylase [ 41 ]. Other molecular docking studies performed for 60 plant-origin compounds revealed that 48 of them have shown binding affinity with lanosterol 14-α-demethylase [ 42 ].…”

Candidíase no cenário brasileiro atual: epidemiologia, prevenção e manejo

“…(JALAGAS ME, et al, 2006) Apesar da eficácia comprovada de todos os antifúngicos descritos, a preocupação com a resistência à cepa considera novas alternativas ao tratamento, no Rio Grande do Sul um estudo constatou a resistência in vitro de 42% dos isolados resistente ao fluconazol oral, enquanto outro em Santa Catarina encontrou 100% de resistência ao mesmo fármaco (BRANDOLT, 2017). A mais recente possível inovação farmacológica encontrada foi acerca do linalol, uma molécula fungicida que afeta a integridade da membrana e da parede celular de C. albicans, porém mais pesquisas devem ser realizadas (MEDEIROS, 2022).…”