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Purpose: The resistance of C. albicans to traditional antifungal drugs brings a great challenge to clinical treatment. To overcome the resistance, developing antifungal agent sensitizers has attracted considerable attention. This study aimed to determine the anti- Candida activity of BEH alone or BEH-FLC combination and to explore the underlying mechanisms., Materials and Methods: In vitro antifungal effects were performed by broth microdilution assay and XTT reduction assay. Infected Galleria mellonella larvae model was used to determine the antifungal effects in vivo. Probes Fluo-3/AM, FITC-VAD-FMK and rhodamine 6G were used to study the influence of BEH and FLC on intracellular calcium concentration, metacaspase activity and drug efflux of C. albicans ., Results: BEH alone exhibited obvious antifungal activities against C. albicans . BEH plus FLC not only showed synergistic effects against planktonic cells and preformed biofilms within 8 h but also enhanced the antifungal activity in infected G. mellonella larvae. Mechanistic studies indicated that antifungal effects of drugs might be associated with the increasement of calcium concentration, activation of metacaspase activity to reduce virulence and anti-biofilms, but were not related to drug efflux., Conclusion: BEH alone or combined with FLC displayed potent antifungal activity both in vitro and in vivo, and the underlying mechanisms were related to reduced virulence factors., Competing Interests: The authors report a patent ZL202010782426.2 licensed to Shujuan Sun; Xueqi Chen; Chunyan Li; Haiying Yan; Hongyao Ren. The authors report no other conflicts of interest in this work., (© 2021 Chen et al.)

Objectives: The resistance of Candida albicans ( C. albicans ) to classical antifungals has been increasing significantly and poses great challenges to clinical treatment. The objective of this research is to evaluate whether the combination of lonidamine (LND) and fluconazole (FLC) have synergistic antifungal activity against C. albicans and to explore the underlying synergistic mechanisms against FLC-resistant C. albicans ., Methods: The antifungal effect on resistant planktonic C. albicans and preformed biofilms were performed by broth microdilution assay and XTT reduction assay. The influence on hyphal growth, cellular ROS level, metacaspase activity and drug transporters were investigated by morphogenesis observation, DCFH-DA, FITC-VAD-FMK and rhodamine6G assay, respectively., Results: LND in combination with FLC exhibited synergistic antifungal effects against resistant planktonic C. albicans and preformed biofilms of C. albicans in the early stages (performed at 4 h and 8 h). The synergistic mechanisms associated with the inhibition of the hyphal growth and the activation of metacaspase, but were not related to mediate cellular ROS level or drug uptake and efflux in resistant C. albicans ., Conclusion: LND combined with FLC exhibited synergistic antifungal activity against resistant C. albicans , and the synergistic mechanisms were related to anti-biofilms and reduce virulence factors., Expert Opinion: The emergence of fluconazole-resistant Candida albicans strains poses great challenges to clinical treatment. Drug combination of non-antifungals and fluconazole has attracted a lot of attention to overcome Candida albicans drug resistance.

The number of invasive fungal infections has increased dramatically over recent years, leading to high morbidity and mortality of immunocompromised patients. Candida albicans is the most common cause of life-threatening disseminated candidiasis among invasive fungal infections. Resistance of C. albicans against conventional antifungals is frequently reported. Treatment with a combination of antifungal and non-antifungal agents is often considered in the aim to overcome drug resistance. This study shows for the first time that the combination of ginkgolide B (GB) and fluconazole (FLC) increases the sensitivity of resistant C. albicans to FLC. In vitro studies indicated that the drug combination had a synergistic effect on C. albicans in both planktonic cells and biofilms within 12 h. In vivo efficacy of this drug combination was evaluated using the Galleria mellonella infection model. Survival rate, fungal burden, and histological examination were determined. Studies indicated that the antifungal effects of GB in combination with FLC might be associated with inhibition of hyphal growth, disruption of intracellular calcium, and inhibition of drug efflux pumps. The results indicate a promising solution for overcoming drug resistance of C. albicans and expanding the clinical application of existing drugs., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Invasive fungal infections are an emerging problem worldwide, which bring huge health challenges. Candida albicans , the most common opportunistic fungal pathogen, can cause bloodstream infections with high mortality in susceptible hosts. At present, available antifungal agents used in clinical practice are limited, and most of them also have some serious adverse effects. The emergence of drug resistance because of the wide use of antifungal agents is a new limitation to successful patient therapy. Drug combination therapy is increasingly becoming a way to enhance antifungal efficacy, and reduce drug resistance and potential toxicity. Panobinostat, as a pan-histone deacetylase inhibitor, has been approved by the United States Food and Drug Administration as novel antitumor agents. In this study, the antifungal effects and mechanisms of panobinostat combined with fluconazole (FLC) against C. albicans were explored for the first time. The results indicated that panobinostat could work synergistically with FLC against resistant C. albicans , the minimal inhibitory concentration (MIC) of panobinostat could decrease from 128 to 0.5–2 μg/ml and the MIC of FLC could decrease from >512 to 0.25–0.5 μg/ml, and the fractional inhibitory concentration index (FICI) value ranged from 0.0024 to 0.0166. It was not only synergized against planktonic cells but also against C. albicans biofilms performed ≤8 h when panobinostat is combined with fluconazole; the sessile MIC (sMIC) of panobinostat could decrease from >128 to 0.5–8 μg/ml and the sMIC of FLC from >1024 to 0.5–2 μg/ml, and the FICI value was <0.5. The Galleria mellonella infection model was used to evaluate the in vivo effect of the drug combination, and the result showed that the survival rate could be improved obviously. Finally, we explored the synergistic mechanisms of the drug combination. The hyphal growth, which plays roles in drug resistance, was found to be inhibited, and metacaspase which is related to cell apoptosis was activated (p < 0.01), whereas the synergistic effects were proven not to be related to the efflux pumps (p > 0.05). These findings might provide novel insights into the antifungal drug discovery and the treatment of candidiasis caused by C. albicans. [ABSTRACT FROM AUTHOR]

Over the last few decades, candidiasis has exhibited an increasing incidence worldwide, causing high mortality in immunocompromised patients. Candida albicans is one of the leading opportunistic fungal pathogens. However, due to the increased use of antifungal agents, resistance of C. albicans to conventional agents, especially fluconazole, has frequently emerged. Therefore, research on the use of combinations of current drugs to sensitize antifungal agents and overcome fungal resistance has attracted considerable attention. This study demonstrated for the first time that D-penicillamine (PCA) combined with fluconazole showed a synergistic effect against C. albicans. PCA combined with fluconazole not only showed synergistic effects against planktonic cells of C. albicans , but also showed synergistic effects against C. albicans biofilms formed within 12 h in vitro. In addition, a Galleria mellonella infection model was used to evaluate the in vivo effects of this drug combination. The results showed that the combination of the two drugs could improve the survival rate, decrease the fungal burden, and reduce the tissue invasion of G. mellonella larvae. Finally, we explored the potential synergistic mechanisms of the drug combination, mainly including inhibition of the morphological transformation, reduction of the intracellular calcium concentration, and the activation of metacaspase, which is closely related to cell apoptosis. These findings might provide novel insights into antifungal drug discovery and the treatment of candidiasis caused by C. albicans. [ABSTRACT FROM AUTHOR]