Silver Nanoparticles Offer a Synergistic Effect with Fluconazole Against Fluconazole-Resistant Candida Albicans by Abrogating Drug Efflux Bumps and Increasing Endogenous ROS

Abstract

Objectives: 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.Methods: 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. Results: The results indicated that AgNPs worked synergistically with fluconazole against both planktonic cells of fluconazole-resistant C. albicans and biofilms formed < 12 hours. 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. Conclusion: In conclusion, these results further confirm that AgNPs-fluconazole combination is a hopeful strategy for the treatment of fluconazole-resistant fungal infections.

In Vitro Antifungal Activity of Silver Nanoparticles Biosynthesized with Beech Bark Extract

“…Another study proved that AgNP treatment of C. albicans down-regulated the CDR2, ERG25, ERG1, and ERG11 expression, reduced the membrane fluidity and ergosterol levels, and produced elevated reactive oxygen species levels, confirming that AgNPs might be an alternative strategy for fluconazole-resistant Candida spp. [60].…”

Silver nanoparticles, a promising treatment against clinically important fluconazole‐resistant Candida glabrata

“…Combination treatment is considered as an attractive strategy that might increase drug efficiency and decrease toxicity through decreasing concentrations of both agents, while overcoming resistance of C. glabrata (Cui et al 2015). The effect of different types of AgNPs on fluconazole activity against C. albicans and other Candida species was reported earlier (Gajbhiye et al 2009;Longhi et al 2015;Samrat et al 2016;Sun et al 2016;Wypij et al 2017;Cunha et al 2018;Hussain et al 2019;Nadhe et al 2019;Sun and Jia 2020). Table 1 showed remarkable effect of the combinations of fluconazole and AgNPs on the strains used, particularly against CBS 138, followed by DSY565, i.e.…”

“…Recently, AgNPs were shown to not only possess antibacterial activity but also to overcome multidrug resistance in bacteria (Cavassin et al 2015). A limited number of studies evaluated the ability of AgNPs to reverse the resistance to fluconazole in fungal cells, particularly Candida species (Gajbhiye et al 2009;Longhi et al 2015;Samrat et al 2016;Sun et al 2016;Wypij et al 2017;Cunha et al 2018;Hussain et al 2019;Nadhe et al 2019;Sun and Jia 2020). Furthermore, we found only one study that investigated the ability of AgNPs to increase susceptibility to fluconazole in C. glabrata (Souza et al 2020).…”