Abstract
Candida albicans is a common opportunistic fungal pathogen that may cause nosocomial fungal infections. The resistance of Candida albicans to traditional antifungal drugs has been increasing rapidly in recent years, and it brings a great challenge in clinical treatment. N-butylphthalide is originally extracted from the seed of Apium graveolens and is currently used for the treatment of ischemic stroke in the clinic. This study demonstrated that n-butylphthalide exhibited antifungal activity against Candida albicans with minimum inhibitory concentrations of 128 μg/ml; moreover, n-butylphthalide combined with fluconazole showed synergistic antifungal effects against resistant Candida albicans, resulting in a decrease in the minimum inhibitory concentrations of fluconazole from >512 to 0.25–1 μg/ml. Time-killing curves verified the antifungal activity in dynamic. Besides, n-butylphthalide exhibited anti-biofilm activity against Candida albicans, biofilms preformed <12 h with sessile minimum inhibitory concentrations of 128–256 μg/ml and synergism was observed when n-butylphthalide combined with fluconazole against resistant Candida albicans biofilms preformed <12 h, resulting in a decrease in the sessile minimum inhibitory concentrations of fluconazole from >1,024 to 0.5–8 μg/ml. Furthermore, in vitro antifungal effects of n-butylphthalide were confirmed in vivo. N-butylphthalide prolonged survival rate of larvae infected by Candida albicans, reduced the fungal burden in larvae and caused less damage to larval tissues. Notably, n-butylphthalide inhibited hyphal growth and induced intracellular reactive oxygen species accumulation and a loss in mitochondrial membrane potential, which was a potential antifungal mechanism. Besides, the synergistic effects between n-butylphthalide and fluconazole potentially relied on the mechanism that n-butylphthalide significantly promoted drug uptake, and suppressed drug efflux via down-regulating the drug transporter encoding genes CDR1 and CDR2. These findings demonstrated the antifungal effects and mechanisms of n-butylphthalide against Candida albicans for the first time, which might provide broad prospects for the identification of new potential antifungal targets.
Highlights
Due to the extensive application of broad-spectrum antibiotics, immunosuppressive agents, and medical implant devices, the incidence of fungal infections has increased rapidly in the last few decades (Suleyman and Alangaden, 2016)
NBP exhibited antifungal activity against C. albicans with minimum inhibitory concentrations (MICs) of 128 μg/ml, and exhibited synergistic effects combined with FLC against resistant C. albicans with fractional inhibitory concentration index (FICI) of 0.25, resulting in a decrease in the MICs of NBP from 128 to 32 μg/ml and the MICs of FLC from >512 to 0.25–1 μg/ml
No synergism was observed with FICIs of >0.5 when NBP combined with FLC against susceptible C. albicans, the MICs of NBP could decrease from 128 to 8–64 μg/ml and the MICs of FLC could decrease from 0.5–1 to 0.25–0.5 μg/ml
Summary
Due to the extensive application of broad-spectrum antibiotics, immunosuppressive agents, and medical implant devices, the incidence of fungal infections has increased rapidly in the last few decades (Suleyman and Alangaden, 2016). The leading Candida species, Candida albicans (C. albicans), is the most common fungal pathogen that may cause epidermal and potentially life-threatening invasive infections, especially in immunocompromised patients (Dimopoulos et al, 2007). Fluconazole (FLC), a kind of azoles, is the most frequently used antifungal drug for prevention and treatment of C. albicans infections due to the high efficacy and low toxicity. Drug resistance to antifungals, especially to FLC among C. albicans species, increased sharply along with long-term use of it (Whaley et al, 2016). There is an urgent need to develop therapeutic strategies to combat drug resistance of C. albicans
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