The Synergistic Antifungal Effect and Potential Mechanism of D-Penicillamine Combined With Fluconazole Against Candida albicans.

Yiman Li,Ping Jiao,Xueqi Chen,Shujuan Sun,Ying Gong,Yuanyuan Li

doi:10.3389/fmicb.2019.02853

Abstract

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.

Highlights

In the last few decades, invasive fungal infections have dramatically increased in immunocompromised individuals including patients with organ transplantation and HIV infection as well as patients undergoing chemotherapy and those subjected to overprescription of steroid therapy (Romano et al, 2017)
The Minimum Inhibitory Concentrations Against Planktonic Cells of Candida albicans The data in Table 1 show that the antifungal effect of PCA alone against C. albicans was not obvious, with an minimum inhibitory concentration (MIC) >256 μg/ml
When PCA and FLC were combined against planktonic cells of C. albicans, the MIC of FLC was significantly reduced, indicating a strong synergistic effect

Summary

Introduction

In the last few decades, invasive fungal infections have dramatically increased in immunocompromised individuals including patients with organ transplantation and HIV infection as well as patients undergoing chemotherapy and those subjected to overprescription of steroid therapy (Romano et al, 2017). Studies have shown that many non-antifungal drugs can significantly increase the sensitivity of azoles most of them do not have a strong antifungal effect by themselves (Liu et al, 2014). Combination therapy may be an optional approach for the treatment of invasive fungal infections, and the potential antifungal mechanisms provide new insights into novel antifungal drug development. Several studies have shown that antifungal effects can be achieved by interfering with ion homeostasis in C. albicans (Liu et al, 2015); there is no report on whether PCA alone has an antifungal effect or acts synergistically with other antifungal drugs. We investigated the effects of PCA alone and in combination with FLC against C. albicans, and its underlying antifungal mechanisms were explored

Methods

Results

Conclusion