Voriconazole-Based Salts Are Active against Multidrug-Resistant Human Pathogenic Yeasts.

Emil Szepiński,Dorota Martynow,Maria J Milewska,Piotr Szweda,Sławomir Milewski

doi:10.3390/molecules24203635

Emil Szepiński, Dorota Martynow + Show 3 more

Open Access

https://doi.org/10.3390/molecules24203635

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Abstract

Voriconazole (VOR) hydrochloride is unequivocally converted into VOR lactates and valinates upon reaction with silver salts of organic acids. This study found that the anticandidal in vitro activity of these compounds was comparable or slightly better than that of VOR. The Candida albicans clinical isolate overexpressing CaCDR1/CaCDR2 genes, highly resistant to VOR, was apparently more susceptible to VOR salts. On the other hand, the susceptibility of another C. albicans clinical isolate (demonstrating multidrug resistance due to the overexpression of CaMDR1) to VOR salts was comparable to that to VOR. Comparative studies on the influence of VOR and its salts on Rhodamine 6G efflux from susceptible and multidrug-resistant C. albicans cells revealed that VOR salts are poorer substrates for the CaCdr1p drug efflux pump than VOR.

Highlights

The emergence of human pathogenic fungi that are resistant to commonly used antifungal drugs is a great challenge for antimicrobial chemotherapy [1]
We present the results of our studies on preparation of VOR saltsexhibiting and their antifungal phenotype.including activity against human pathogenic yeasts exhibiting the MDR phenotype
Susceptibility of the B3 and B4 cells to VOR salts 2 and 5a–d was nearly identical as to VOR, whereas the minimal inhibitory concentrations (MIC) values of VOR salts against the Gu5 strain were 8–16 times lower than that of VOR, while the MIC values against the Gu4 strain were only 2–4 times lower. These results show that the C. albicans MDR, due to overexpression of the CDR1/CDR2 genes, can be more effectively overcome by VOR salts than by VOR itself

Summary

Introduction

The emergence of human pathogenic fungi that are resistant to commonly used antifungal drugs is a great challenge for antimicrobial chemotherapy [1]. Earlier reports indicated that the conversion of azole and triazole antifungals—ketoconazole, fluconazole, tebuconazole and propiconazole—into respective ionic forms upon protonation of the nitrogen atoms in the azole or triazole ring and combination with the appropriate anion may result in improvement of the antifungal properties of the obtained salts, in comparison with the mother compounds [7,8,9] Some of these salts exhibit physicochemical properties that are attributed to ionic liquids, especially the liquid state of matter at room temperature [7,8]. We present the results of our studies on preparation of VOR saltsexhibiting and their antifungal phenotype.including activity against human pathogenic yeasts exhibiting the MDR phenotype

Chemistry

Antifungal Activity of VOR Salts

Preparation of Voriconazole-Based Salts

Microorganisms and Growth Conditions

Determination of Antifungal In Vitro Activity

Conclusions