Step-wise evolution of azole resistance through copy number variation followed by KSR1 loss of heterozygosity in Candida albicans
Antimicrobial drug resistance poses a global health threat, requiring a deeper understanding of the evolutionary processes that lead to its emergence in pathogens. Complex evolutionary dynamics involve multiple mutations that can result in cooperative or competitive (clonal interference) effects. Candida albicans, a major fungal pathogen, displays high rates of copy number variation (CNV) and loss of heterozygosity (LOH). CNV and LOH events involve large numbers of genes and could synergize during evolutionary adaptation. Understanding the contributions of CNV and LOH to antifungal drug adaptation is challenging, especially in the context of whole-population genome sequencing. Here, we document the sequential evolution of fluconazole tolerance and then resistance in a C. albicans isolate involving an initial CNV on chromosome 4, followed by an LOH on chromosome R that involves KSR1. Similar LOH events involving KSR1, which encodes a reductase in the sphingolipid biosynthesis pathway, were also detected in independently evolved fluconazole resistant isolates. We dissect the specific KSR1 codons that affect fluconazole resistance and tolerance. The combination of the chromosome 4 CNV and KSR1 LOH results in a >500-fold decrease in azole susceptibility relative to the progenitor, illustrating a compelling example of rapid, yet step-wise, interplay between CNV and LOH in drug resistance evolution.
Authors
- Corinne Maufrais (ORCID: https://orcid.org/0000-0002-8718-0432)
- Scott G. Filler (ORCID: https://orcid.org/0000-0001-7278-3700)
- Cécile Gautier (ORCID: https://orcid.org/0009-0008-2789-1815)
- Eli Isael Maciel (ORCID: https://orcid.org/0000-0002-0939-761X)
- Pétra Vande Zande (ORCID: https://orcid.org/0000-0002-4789-9899)
- Judith Berman (ORCID: https://orcid.org/0000-0002-8577-0084)
- Iuliana V. Ene (ORCID: https://orcid.org/0000-0002-0390-7084)
- Anna Selmecki (ORCID: https://orcid.org/0000-0003-3298-2400)
- Nora Kawar
- Katura Metzner (ORCID: https://orcid.org/0000-0003-1207-6216)
- Maurizio Del Poeta (ORCID: https://orcid.org/0000-0001-8418-3120)
- Norma V. Solis (ORCID: https://orcid.org/0000-0001-5163-2110)
- Caroline Mota Fernandes
- Annette K. Beach
- Nívea Pereira de Sá (ORCID: https://orcid.org/0000-0003-0901-6909)
- Elizabeth Wash
- Ryan Bracken
Institutions
- University of Minnesota (US)
- Institut Pasteur (FR)
- University of California, Los Angeles (US)
- Tel Aviv University (IL)
- Université Paris Cité (FR)
- UCLA Medical Center (US)
- Northport VA Medical Center (US)
- Harbor–UCLA Medical Center (US)
- Stony Brook University (US)
Publication Details
- Journal
- PLoS Pathogens
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1371/journal.ppat.1012497
- Citations
- 17
- Primary Topic
- Antifungal resistance and susceptibility
- Type
- article
- Field-Weighted Citation Impact
- 6.22
Funders
- U.S. Department of Veterans Affairs
- Burroughs Wellcome Fund
- Jane Coffin Childs Memorial Fund for Medical Research
- University of Minnesota
- Canadian Institute for Advanced Research
- European Commission
- Agence Nationale de la Recherche
- National Institute of Allergy and Infectious Diseases
- H2020 European Research Council