npj Antimicrobials and Resistance (Sep 2024)

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

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

DOI
https://doi.org/10.1038/s44259-024-00041-8
Journal volume & issue
Vol. 2, no. 1
pp. 1 – 8

Abstract

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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.