5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus
Year: 2020
Type: article
Abstract: Drug resistance is a critical challenge in treating infectious disease. For fungal infections, this issue is exacerbated by the limited number of available and effective antifungal agents. Patients infected with the fungal pathogen Cryptococcus are most effectively treated with a combination of amphotericin B and 5-fluorocytosine (5FC). Isolates causing infections frequently develop resistance to 5FC although the mechanism of this resistance is poorly understood. Here we show that resistance is acquired more frequently in isolates with defects in DNA mismatch repair that confer an elevated mutation rate. Natural isolates of Cryptococcus with mismatch repair defects have recently been described and defective mismatch repair has been reported in other pathogenic fungi. In addition, whole genome sequencing was utilized to identify mutations associated with 5FC resistance in vitro . Using a combination of candidate-based Sanger and whole genome Illumina sequencing, the presumptive genetic basis of resistance in 16 independent isolates was identified, including mutations in the known resistance genes FUR1 and FCY2 , as well as a novel gene, UXS1 . Mutations in UXS1 lead to accumulation of a metabolic intermediate that appears to suppress toxicity of both 5FC and its toxic derivative 5FU. Interestingly, while a UXS1 ortholog has not been identified in other fungi like Saccharomyces cerevisiae , where the mechanisms underlying 5FC and 5FU resistance were elucidated, a UXS1 ortholog is found in humans, suggesting that mutations in UXS1 in cancer cells may also play a role in resistance to 5FU when used during cancer chemotherapy in humans.
Source: Nature Communications
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,380
Awards: Genetics of Cryptococcus sexual reproduction, G1072885028, G1135287008, G1187870902, G1394274318, G1443874385, Structure, function, and evolution of the Cryptococcus MAT locus, G1825851999, G2615831811, G2895017123, G316281995, G3303573839, G4471561644, Role of glycan precursor transporters in Cryptococcus neoformans virulence, G5175906424, GLYCAN PRECURSOR TRANSPORT IN CRYPTOCOCCUS NEOFORMANS, G5520316217, G5562136253, G5598445083, Transdisciplinary Program to Identify Novel Antifungal Targets and Inhibitors, CRYPTOCOCCAL GLYCAN SYNTHESIS, G6521366149, G7391070412, G7788159555, G7794633445, G8021174655, G8052145414, Structural Biological Development of Fungal-Specific Calcineurin Inhibitors, Structural Biological Development of Fungal-Specific Calcineurin Inhibitors, G9000046215, G9000118478, G9000137177, G9000213338, G9000251427, G9000337182, G9000341885, Cryptococcus genomic resources, Impact of RNAi and unisexual reproduction on Cryptococcus evolution, drug resistance, and pathogenesis
OpenAlex ID: W3000052441