Abstract
A frequent emergence of drug resistance has been observed and posed great threat to global public health recently. This work aimed to investigate the potential synergistic effect and the underlying mechanisms of AgNPs-fluconazole combination more extensively through 2 clinically isolated fluconazole-resistant Candida albicans (C. albicans) strains. Antifungal properties of AgNPs and fluconazole alone or together against planktonic cells and biofilms were tested. Cellular and molecular targets associated with fluconazole resistance were monitored after AgNPs treatment. Antifungal potential of AgNPs-fluconazole combination was also explored in vivo using a mouse model of disseminated candidiasis. Tissue burden and survival rate were analyzed. The results indicated that AgNPs worked synergistically with fluconazole against both planktonic cells of fluconazole-resistant C. albicans and biofilms formed <12h. AgNPs treatment down-regulated ERG1, ERG11, ERG25, and CDR2, decreased membrane ergosterol levels and membrane fluidity, reduced membrane content of Cdr1p, Cdr2p, and thus efflux bump activity. The elevated ROS production was also a likely cause of the synergistic effect. In vivo, AgNPs and fluconazole combination significantly decreased the fungal burden and improved the survival rate of infected mice. In conclusion, these results further confirm that AgNPs-fluconazole combination is a hopeful strategy for the treatment of fluconazole-resistant fungal infections.
Highlights
The word-wide emergence of antifungal resistance among fungus has posed great threat to global public health [1, 2]
The results indicated that AgNPs worked synergistically with fluconazole against both planktonic cells of fluconazole-resistant C. albicans and biofilms formed < 12 hours
AgNPs could induce intracellular ROS production [31]. These factors are essential for drug resistance in the fungal cells [32, 33] in this study, we aimed to study the antifungal activity of AgNPs-fluconazole combination more extensively, both in vitro and in vivo and tried to investigate if AgNPs treatment could sensitize resistant C. albicans to fluconazole by targeting these cellular molecules and events related to drug resistance
Summary
The word-wide emergence of antifungal resistance among fungus (resistance towards conventional used antimicrobials) has posed great threat to global public health [1, 2]. Despite the great advance in the development of antifungal drugs, infections by Candida species including C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei still cause great morbidity and mortality [5]. Among these species, C. albicans constitutes the most problematic and prevalent one accounting for nearly 50% of candidiasis. Fluconazole is the most widely used antifungal drug for the treatment of fungal infections because of its low cost, low toxicity and high efficacy. Various multi-drug resistant, especially fluconazole resistant C. albicans have been reported [9]. Much progress has been made in understanding the reasons responsible for antifungal resistance in C. albicans. Design or discovery of new antifungal drugs that target these multiple cellular targets may offer us a chance to break drug resistance
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