Abstract
Effective management and treatment of fungal diseases is hampered by poor diagnosis, limited options for antifungal therapy, and the emergence of antifungal drug resistance. An understanding of molecular mechanisms contributing to resistance is essential to optimize the efficacy of currently available antifungals. In this perspective, one of the oldest antifungals, 5-fluorocytosine (5-FC), has been the focus of recent studies applying advanced genomic and transcriptomic techniques to decipher the order of events at the molecular level that lead to resistance. These studies have highlighted the complexity of resistance and provided new insights that are reviewed in the present paper.
Highlights
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Dodgson et al [31] showed that both decreased susceptibility and increased resistance mostly correlate with a single change from cytosine to thymine at position 301 of the FUR1 gene
Edlinde et al [39] confirmed, by isolating the mutants in URA3 strains and testing their ability to assimilate the cytosine, that the mutants are null. They found some of these mutations (FUR1 G210D and L136R, FCY1 T84L, and FCY2J I384F) in clinical isolates. 5-FC-azole antagonism was described in C. glabrata as a result of upregulation of the Pdr1-dependent CDR1 induced by 5-FC [64]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Management and appropriate treatment of fungal infections remains a challenge that is aggravated by the emergence of antifungal resistance [1,2]. Elucidation of the molecular mechanisms of antifungal resistance may help to develop better diagnostic approaches and new therapeutic strategies that can overcome resistance and optimize the treatment efficacity. The drug is significant for treatment of fungal infections at body sites with limited drug penetration of other antifungal agents, such as infections of the urinary tract, brain and eyes, or heart valves [5]. Resistance to 5-FC is well known, the genetic basis of resistance regulation has remained enigmatic An understanding of these mechanisms may help to discover novel ways to reduce or reverse resistance and broaden the clinical use of this drug, benefiting from its excellent tissue distribution. We discuss the mode of action of 5-FC and give an overview of the current resistance mechanisms that have been reported in the literature
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