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

Area of Science:

• Mycology
• Medicinal Chemistry
• Pharmacology

Background:

• Voriconazole (VOR) is a key antifungal agent.
• Drug resistance in Candida albicans, particularly through efflux pumps like CaCdr1p, limits VOR efficacy.
• Novel formulations are needed to overcome resistance mechanisms.

Purpose of the Study:

• To synthesize and characterize voriconazole lactates and valinates.
• To evaluate the in vitro anticandidal activity of VOR salts compared to VOR.
• To investigate the susceptibility of multidrug-resistant Candida albicans strains to VOR salts.

Main Methods:

• Synthesis of VOR lactates and valinates using silver salts of organic acids.
• In vitro antifungal susceptibility testing against Candida albicans isolates.
• Assessment of Rhodamine 6G efflux in susceptible and resistant strains.

Main Results:

• VOR salts exhibited anticandidal activity comparable or superior to VOR.
• VOR salts were more effective against a VOR-resistant Candida albicans isolate overexpressing CaCDR1/CaCDR2.
• Susceptibility to VOR salts was similar to VOR in a CaMDR1-overexpressing isolate.
• VOR salts were less efficiently effluxed by the CaCdr1p pump than VOR.

Conclusions:

• Voriconazole salts represent a promising alternative for treating Candida albicans infections.
• VOR salts may overcome specific drug resistance mechanisms mediated by the CaCdr1p efflux pump.
• Further investigation into VOR salts is warranted for clinical application.