Antifungal Activity And Mechanism Of Coordination Complex And Combination Based On Voriconazole

Antifungal agent resistance is a difficult problem for the international community at present.Voriconazole,a first-line clinical antifungal agent,has appeared drug resistance.High-risk patients have low resistance to resistant fungi is particularly worrisome.Therefore,with the increasing number of drug-resistant fungi in clinic,there is an urgent to develop new therapeutic strategies or antifungal agents.On one hand,we adopt the idea of using Ag（I）-voriconazole coordination complex.Two new polymeric silver（I）complexes with voriconazole（Vor）,namely[Ag（Vor）₂]_n（Cl O₄）_n（1）and[Ag₂（Vor）₄]_n（NO₃）_2n（2）,were synthesized.On the other hand,we adopt the idea of combining voriconazole with Ag-NPs.Ag-NPs with different particle sizes（20,30 and 50 nm）were synthesized and characterized.The in vitro antifungal activity of the ideas mentioned above was evaluated comprehensively by using the minimum inhibitory concentration and the growth inhibition kinetic curve.The fractional inhibitory concentration index was used to evaluate the interaction between the components of the complex and the combination of vor and Ag-NPs.The silver（I）-voriconazole complexes have good antifungal activity against common pathogenic fungi（Candida spp.and Aspergillus spp.）.Compared with voriconazole,the complexes have higher antifungal activity against voriconazole-resistant Candida albicans strains,inhibiting the growth in a dose-dependent manner.The silver salt and voriconazole in the complex exert an synergistic antifungal effect.Compared with 20 and 30 nm Ag-NPs,the antifungal activity of Ag-NPs with the size of 50 nm was slightly worse.When combined with voriconazole,Ag-NPs with three different sizes could play a strong synergistic antifungal effect on both voriconazole-sensitive and voriconazole-resistant strains,and the growth inhibition kinetic curve was similar.The Ag（I）-voriconazole complex combines the advantages of the silver ions and voriconazole,showing synergistic antifungal effects.Their mechanism might rely on the fact that Ag（I）ion enhanced the cell membrane permeability,improved voriconazole into the cell and inhibit the efflux pump activity to maintain the concentration of intracellular voriconazole.Therefore,when exposed to silver（I）-voriconazole complexes,the mitochondrial respiratory function and hyphae formation in Candida albicans was inhibited.The antifungal mechanism of the combination of Ag-NPs and voriconazole may be as follows:destroying the normal cell structure of fungi,stimulating the increase of ROS level in cells,inhibiting the occurrence and development of hyphae,and down-regulating the expression of CDR1 and CDR2 related to azole resistance,which helps to maintain the effective concentration of intracellular drugs.The expression of ACT1 gene was down-regulated as well,which increase the permeability of cell membranes and sensitive to the external environment.This study shows that Ag（I）-voriconazole complex or the combination of Ag-NPs and voriconazole,can play a synergistic antifungal role,which is of great significance for further research.It is helpful to solve the problem of voriconazole resistance of clinical fungi and provides research ideas for follow-up research.