Genetic mutations in Cryptococcus neoformans pyrimidine salvage pathway enzymes contribute to reduced susceptibility against 5-fluorocytosine

Cryptococcal meningitis is a high-mortality infection. Adding 5-fluorocytosine (5-FC) to its treatment improves outcomes, but resistance to 5-FC presents a significant challenge. We conducted whole-genome sequencing on seven C. neoformans isolates with varying 5-FC susceptibility, along with proteomic and in silico analyses. Our findings indicate that mutations in genes of the pyrimidine salvage pathway are responsible for 5-FC resistance. Specifically, we identified an E64G missense mutation in the FUR1 gene, a large deletion in the FCY1 gene, and a point mutation in FCY1 leading to a truncated protein. The proteomic data indicated that these mutations resulted in the absence or reduction of crucial enzymes in resistant isolates. Genetic transformations confirmed the association between these mutations and 5-FC resistance. Resistance to 5-FC can develop during treatment and is closely tied to mutations in key metabolic enzymes. Understanding in vivo resistance development is crucial for combating resistance and enhancing patient outcomes.

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Publication Details

Journal
npj Antimicrobials and Resistance
Published
2024-09-10
DOI
https://doi.org/10.1038/s44259-024-00041-8
Citations
3
Primary Topic
Fungal Infections and Studies
Type
article
Field-Weighted Citation Impact
1.16

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article

Genetic mutations in Cryptococcus neoformans pyrimidine salvage pathway enzymes contribute to reduced susceptibility against 5-fluorocytosine

Willem J. G. Melchers, Jordy P. M. Coolen, Fatima Zohra Delma, Jochem B. Buil et al.
3 citations
npj Antimicrobials and Resistance
Fungal Infections and Studies
1.16
article

Genetic mutations in Cryptococcus neoformans pyrimidine salvage pathway enzymes contribute to reduced susceptibility against 5-fluorocytosine

Willem J. G. Melchers, Jordy P. M. Coolen, Fatima Zohra Delma, Jochem B. Buil, Yun C. Chang, Sarah Ahmed, Paul E. Verweij, Alfredo Cabrera‐Orefice, Abdullah M. S. Al‐Hatmi, Sybren de Hoog, Dong-Hoon Yang, Kyung J. Kwon‐Chung
article en
3 citations

Abstract

Cryptococcal meningitis is a high-mortality infection. Adding 5-fluorocytosine (5-FC) to its treatment improves outcomes, but resistance to 5-FC presents a significant challenge. We conducted whole-genome sequencing on seven C. neoformans isolates with varying 5-FC susceptibility, along with proteomic and in silico analyses. Our findings indicate that mutations in genes of the pyrimidine salvage pathway are responsible for 5-FC resistance. Specifically, we identified an E64G missense mutation in the FUR1 gene, a large deletion in the FCY1 gene, and a point mutation in FCY1 leading to a truncated protein. The proteomic data indicated that these mutations resulted in the absence or reduction of crucial enzymes in resistant isolates. Genetic transformations confirmed the association between these mutations and 5-FC resistance. Resistance to 5-FC can develop during treatment and is closely tied to mutations in key metabolic enzymes. Understanding in vivo resistance development is crucial for combating resistance and enhancing patient outcomes.

npj Antimicrobials and ResistanceVol. 2(1)
Radboud University Nijmegen (NL), University of Nizwa (OM), Radboud University Medical Center (NL), Radboud Institute for Molecular Life Sciences (NL), National Institute of Allergy and Infectious Diseases (US)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institute of Allergy and Infectious Diseases, NHLBI Division of Intramural Research
Zero hunger
Openalex Percentile: Top 20%
Fungal Infections and Studies
1.16
DOIOpen Access PDFOpenAlex
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