Synergistic Antifungal Effect of Fluconazole Combined with Licofelone against Resistant Candida albicans.

Xinning Liu,Shujuan Sun,Wenwen Sun,Jianqiao Liu,Yilei Yang,Tao Li,Decai Wang

doi:10.3389/fmicb.2017.02101

Abstract

Candida albicans (C. albicans) is one of the important opportunistic fungal pathogens that is closely associated with disseminated or chronic infections. The objective of this study is to evaluate the synergistic antifungal effect of licofelone, which is dual microsomal prostaglandin E2 synthase/lipoxygenase (mPGES-1/LOX) inhibitor in combination with fluconazole against C. albicans. Here our results showed that licofelone (16 μg/mL) can synergistically work with fluconazole (1 μg/mL) against planktonic cells of fluconazole-resistant C. albicans. The two-drug combination inhibited the C. albicans biofilm formation over 12 h, and reduced the expression of extracellular phospholipase genes, biofilm-specific genes and RAS/cAMP/PKA pathway related genes. In addition, the two-drug combination inhibited the transition from yeast to hyphal growth form, and decreased the secreted aspartyl proteinase activity, while not affecting the drug efflux pumps activity. Galleria mellonella model was also used to confirm the antifungal activity of the drug combination in vivo. This study first indicates that the combination of fluconazole and licofelone has synergistic effect against resistant C. albicans and could be a promising therapeutic strategy for the antifungal treatment.

Highlights

Candida albicans is one of the important fungal pathogens that forms biofilm on the surface of catheters and other medical devices
Susceptibility assay showed that the combination of licofelone and fluconazole has strong synergistic antifungal effects against resistant C. albicans: the MIC80 of fluconazole alone against resistant C. albicans (CA10, CA16) were >512 μg/mL, whereas when combined with licofelone (16 μg/mL), the minimal inhibitory concentration (MIC) of fluconazole were decreased to 1 and 0.5, respectively
These effects were illustrated by the fractional inhibitory concentration index (FICI) in vitro: the FICI for the resistant C. albicans (CA10, CA16) strains is 0.127 and 0.250, respectively (Table 1), the FICI of sensitive C. albicans (CA4, CA8) and non-albicans (CG2, CG3, CP2, CP3) strains were all >0.5, indicating that the two-drug combination exhibited no antifungal activity against the sensitive C. albicans and non-albicans

Summary

Introduction

Candida albicans is one of the important fungal pathogens that forms biofilm on the surface of catheters and other medical devices. Amphotericin B is a potent antifungal agent against an array of yeast and filamentous fungal pathogens, the application is limited by the significant toxicities such as renal toxicity, infusion reactions, and hepatotoxicity (Clements and Peacock, 1990). Both amphotericin B and echinocandin drugs have minimal gastrointestinal absorption and are only available as parenteral formulations, while fluconazole, one of the commonly used first-line drug of the azole family in clinical prevention and treatment of Candida infections, is readily absorbed with high bioavailability (Nett and Andes, 2016).

Objectives

Methods

Results