Abstract
Candida albicans is a ubiquitous clinical fungal pathogen. Prolonged use of the first-line antifungal agent fluconazole (FLC) has intensified fungal resistance and limited its effectiveness for the treatment of fungal infections. The combined administration of drugs has been extensively studied and applied. SWL-1 is a lignin compound derived from the Traditional Chinese Medicine Schisandra chinensis. In this study, we show that SWL-1 reverses resistance to fluconazole in C. albicans when delivered in combination, with a sharp decrease in the IC50 of fluconazole from >200 to 3.74 ± 0.25 μg/ml, and also reverses the fluconazole resistance of C. albicans in vitro, with IC50 from >200 to 5.3 ± 0.3 μg/ml. Moreover, killing kinetics curves confirmed the synergistic effects of fluconazole and SWL-1. Intriguingly, when SWL-1 was administered in combination with fluconazole in a mouse model of systemic infection, the mortality of mice was markedly decreased and fungal colonization of the kidney and lung was reduced. Further mechanistic studies showed that SWL-1 significantly decreased intracellular adenosine 5’-triphosphate (ATP) levels and inhibited the function of the efflux pump responsible for fluconazole resistance of C. albicans. Proteomic analysis of the effects of SWL-1 on C. albicans showed that several enzymes were downregulated in the glycolytic pathway. We speculate that SWL-1 significantly decreased intracellular ATP levels by hindering the glycolysis, and the function of the efflux pump responsible for fluconazole resistance of C. albicans was inhibited, resulting in restoration of fluconazole sensitivity in FLC-resistant C. albicans. This study clarified the effects and mechanism of SWL-1 on C. albicans in vitro and in vivo, providing a novel approach to overcoming fungal resistance.
Highlights
Candida albicans is an important opportunistic etiological commensal organism in humans
No interaction between SWL-1 combined with FLC was observed on the C. albicans standard and clinically sensitive strains, with fractional inhibitory concentration index (FICI) ranging from 0.93 to 3.23
SWL-1 and FLC individually had no significant inhibitory effect on the growth of FLC-resistant strains, while SWL-1 combined with FLC exhibited potent antifungal activity against FLC-resistant strains, with IC50s of 3.74–28.28 μg/ml, and FICIs of 0.13–0.38, indicating a strong synergistic effect
Summary
Candida albicans is an important opportunistic etiological commensal organism in humans. It resides asymptomatically in the digestive and vaginal mucosae in humans and causes only superficial infection in some people (Gow and Yadav, 2017). Prolonged and widespread use of antifungal drugs, especially the first-line antifungal azoles drugs, has contributed to serious resistance, which has become an obstacle to the treatment of fungal infections worldwide (Alexander and Perfect, 1997; Prasad et al, 2019). The currently available agents are limited, and the development of new antifungal drug is slow and costly. New therapeutic drugs and antifungal methods are urgently required
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