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Elevated mutation rates in multi-azole resistant Aspergillus fumigatus drive rapid evolution of antifungal resistance

Author

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  • Michael J. Bottery

    (University of Manchester)

  • Norman Rhijn

    (University of Manchester)

  • Harry Chown

    (University of Manchester
    Imperial College London)

  • Johanna L. Rhodes

    (Radboud University Medical Centre)

  • Brandi N. Celia-Sanchez

    (University of Georgia)

  • Marin T. Brewer

    (University of Georgia)

  • Michelle Momany

    (University of Georgia)

  • Matthew C. Fisher

    (Imperial College London)

  • Christopher G. Knight

    (The University of Manchester)

  • Michael J. Bromley

    (University of Manchester)

Abstract

The environmental use of azole fungicides has led to selective sweeps across multiple loci in the Aspergillus fumigatus genome causing the rapid global expansion of a genetically distinct cluster of resistant genotypes. Isolates within this cluster are also more likely to be resistant to agricultural antifungals with unrelated modes of action. Here we show that this cluster is not only multi-azole resistant but has increased propensity to develop resistance to next generation antifungals because of variants in the DNA mismatch repair system. A variant in msh6-G233A is found almost exclusively within azole resistant isolates harbouring the canonical cyp51A azole resistance allelic variant TR34/L98H. Naturally occurring isolates with this msh6 variant display up to 5-times higher rate of mutation, leading to an increased likelihood of evolving resistance to other antifungals. Furthermore, unlike hypermutator strains, the G233A variant conveys no measurable fitness cost and has become globally distributed. Our findings further suggest that resistance to next-generation antifungals is more likely to emerge within organisms that are already multi-azole resistant due to close linkage between TR34/L98H and msh6-G233A, posing a major problem due to the prospect of dual use of novel antifungals in clinical and agricultural settings.

Suggested Citation

  • Michael J. Bottery & Norman Rhijn & Harry Chown & Johanna L. Rhodes & Brandi N. Celia-Sanchez & Marin T. Brewer & Michelle Momany & Matthew C. Fisher & Christopher G. Knight & Michael J. Bromley, 2024. "Elevated mutation rates in multi-azole resistant Aspergillus fumigatus drive rapid evolution of antifungal resistance," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54568-5
    DOI: 10.1038/s41467-024-54568-5
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    1. Kelley R. Healey & Yanan Zhao & Winder B. Perez & Shawn R. Lockhart & Jack D. Sobel & Dimitrios Farmakiotis & Dimitrios P. Kontoyiannis & Dominique Sanglard & Saad J. Taj-Aldeen & Barbara D. Alexander, 2016. "Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance," Nature Communications, Nature, vol. 7(1), pages 1-10, September.
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    3. Céline M. O’Gorman & Hubert T. Fuller & Paul S. Dyer, 2009. "Discovery of a sexual cycle in the opportunistic fungal pathogen Aspergillus fumigatus," Nature, Nature, vol. 457(7228), pages 471-474, January.
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