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IntroductionThe increasing resistance of Candida albicans (C. albicans) to conventional antifungal drugs poses a great challenge to the clinical treatment of infections caused by this yeast. Drug combinations are a potential therapeutic approach to overcome the drug- resistance of C. albicans. This study explored the synergistic effects of amantadine hydrochloride (AMH) combined with azole antifungal drugs against drug-resistant C. albicans in vitro and in vivo.MethodsThe in vitro sensitivity of Candida spp. to drugs was determined by the microdilution method. The effect of drugs on the efflux pump activity of C. albicans was determined by the rhodamine 6G tracer method. The egg yolk agar plate method was used to determine the activity of extracellular phospholipase, a C. albicans virulence factor. The Galleria mellonella model of C. albicans infection was used to test the in vivo efficacy of the combination therapy.ResultsIn vitro experiments showed that combinations of AMH with azole antifungal drugs had synergistic antifungal effects on planktonic cells of drug-resistant C. albicans, with fractional inhibitory concentration index values of

IntroductionCandida albicans is the primary cause of systemic candidiasis, which is involved in high morbidity and mortality. Drug resistance exacerbates these problems. In addition, there are limited antifungal drugs available. In order to solve these problems, combination therapy has aroused great interest. Teriflunomide is an immunosuppressant. In the present work, we aimed to identify whether teriflunomide can reverse the resistance of Candida albicans in the presence of sub-inhibitory concentrations of fluconazole in vitro and in vivo.MethodsSeven Candida albicans isolates were used in this study. Susceptibility of Candida albicans in vitro to the drugs was determined using a checkerboard microdilution assay in accordance with the recommendations of the Clinical and Laboratory Standards Institute. The effects of drugs on biofilm biomass of Candida albicans were determined by crystal violet staining. The development ability of Candida albicans hyphae was performed using a modified broth microdilution method. Galleria mellonella was used for testing the in vivo efficacy of the combination therapies. ResultsWe found that the combination of teriflunomide (64 µg/mL) and fluconazole (0.5-1 µg/mL) has a significant synergistic effect in all resistant Candida albicans isolates (n=4). Also, this drug combination could inhibit the immature biofilm biomass and hyphae formation of resistant Candida albicans. Galleria mellonella was used for testing the in vivo efficacy of this combination therapies. As for the Galleria mellonella larvae infected by resistant Candida albicans, teriflunomide (1.6 µg/larvae) combined with fluconazole (1.6 µg/larvae) significantly increased their survival rates, and reduced the fungal burden, as well as damage of tissue in comparison to that in the control group or drug monotherapy group. ConclusionThese results expand our knowledge about the antifungal potential of teriflunomide as an adjuvant of existing antifungal drugs, and also open new perspectives in the treatment of resistant Candida albicans based on repurposing clinically available nonantifungal drugs.

Mulberry leaves are served not only as fodder for silkworms but also as potential functional food, exhibiting nutritional and medical benefits due to the complex and diverse constituents, including alkaloids, flavonoids, phenolic acids, and benzofurans, which possess a wide range of biological activities, such as anti-diabete, anti-oxidant, anti-inflammatory, and so on. Nevertheless, compared with the well-studied phytochemistry and pharmacology of mulberry leaves, the current understanding of the biosynthesis mechanisms and regulatory mechanisms of active ingredients in mulberry leaves remain unclear. Natural resources of these active ingredients are limited owing to their low contents in mulberry leaves tissues and the long growth cycle of mulberry. Biosynthesis is emerging as an alternative means for accumulation of the desired high-value compounds, which can broaden channels for their large-scale green productions. Therefore, this review summarizes the recent research advance on the correlative key genes, enzyme biocatalytic reactions and biosynthetic pathways of valuable natural ingredients (i.e. alkaloids, flavonoids, phenolic acids, and benzofurans) in mulberry leaves, thereby offering important insights for their further biomanufacturing.

Introduction: Candida albicans is the primary cause of systemic candidiasis, which is involved in high morbidity and mortality. Drug resistance exacerbates these problems. In addition, there are limited antifungal drugs available. In order to solve these problems, combination therapy has aroused great interest. Teriflunomide is an immunosuppressant. In the present work, we aimed to identify whether teriflunomide can reverse the resistance of Candida albicans in the presence of sub-inhibitory concentrations of fluconazole in vitro and in vivo. Methods: Seven Candida albicans isolates were used in this study. Susceptibility of Candida albicans in vitro to the drugs was determined using a checkerboard microdilution assay in accordance with the recommendations of the Clinical and Laboratory Standards Institute. The effects of drugs on biofilm biomass of Candida albicans were determined by crystal violet staining. The development ability of Candida albicans hyphae was performed using a modified broth microdilution method. Galleria mellonella was used for testing the in vivo efficacy of the combination therapies. Results: We found that the combination of teriflunomide (64 µg/mL) and fluconazole (0.5-1 µg/mL) has a significant synergistic effect in all resistant Candida albicans isolates (n=4). Also, this drug combination could inhibit the immature biofilm biomass and hyphae formation of resistant Candida albicans. Galleria mellonella was used for testing the in vivo efficacy of this combination therapies. As for the Galleria mellonella larvae infected by resistant Candida albicans, teriflunomide (1.6 µg/larvae) combined with fluconazole (1.6 µg/larvae) significantly increased their survival rates, and reduced the fungal burden, as well as damage of tissue in comparison to that in the control group or drug monotherapy group. Conclusion: These results expand our knowledge about the antifungal potential of teriflunomide as an adjuvant of existing antifungal drugs, and also open new perspectives in the treatment of resistant Candida albicans based on repurposing clinically available nonantifungal drugs. [ABSTRACT FROM AUTHOR]

Background: The limited availability of antifungal drugs for candidiasis and the persistent problem of drug resistance, necessitates the urgent development of new antifungal drugs and alternative treatment options. Research design and methods: This study examined the synergistic antifungal activity of the combination of eravacycline (ERV) and fluconazole (FLC) both in vitro by microdilution checkerboard assay and in vivo by Galleria mellonella model. The underlying synergistic mechanisms of this drug combination was investigated using RNA-sequencing and qPCR. Results: ERV (2 μg/mL) + FLC (0.25–0.5 μg/mL) had strong synergistic antifungal activity against resistant Candida albicans (C. albicans) in vitro, as evidenced by a fractional inhibitory concentration index of 0.0044–0.0088. In vivo experiments in Galleria mellonella larvae infected with resistant C. albicans revealed that ERV (2 μg/larva) + FLC (1 μg/larva) improved survival rates and reduced fungal burden. The results of RNA-sequencing and qPCR showed that the mechanism of synergistic inhibition on resistant C. albicans was related to the inhibition of DNA replication and cell meiosis. Conclusions: These results indicate that the combination of ERV and FLC effectively inhibits resistant C. albicans both in vitro and in vivo and lay the foundation for a potential novel treatment option for candidiasis. [ABSTRACT FROM AUTHOR]