Open AccessFluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans
Author(s) -
Elizabeth W Hunsaker,
Katherine J. McAuliffe,
Katherine J. Franz
Publication year - 2020
Publication title -
jbic. journal of biological inorganic chemistry/jbic, journal of biological and inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.802
H-Index - 101
eISSN - 1432-1327
pISSN - 0949-8257
DOI - 10.1007/s00775-020-01796-x
Subject(s) - azole , fluconazole , candida albicans , chemistry , corpus albicans , antifungal , pharmacology , microbiology and biotechnology , triazole , fungal pathogen , pathogen , biology , organic chemistry
Azole antifungals are an important class of antifungal drugs due to their low cost, ability to be administered orally, and broad-spectrum activity. However, their widespread and long-term use have given rise to adaptation mechanisms that render these compounds less effective against common fungal pathogens, including Candida albicans. New antifungals are desperately needed as drug-resistant strains become more prevalent. We recently showed that copper supplementation potentiates the activity of the azole antifungal fluconazole against the opportunistic fungal pathogen C. albicans. Here, we report eight new azole analogues derived from fluconazole in which one triazole group has been replaced with a metal-binding group, a strategy designed to enhance potentiation of azole antifungal activity by copper. The bioactivity of all eight compounds was tested and compared to that of fluconazole. Three of the analogues showed activity against C. albicans and two had lower levels of trailing growth. One compound, Flu-TSCZ, was found to impact the levels, speciation, and bioavailability of cellular metals.