TY - JOUR
T1 - Step-wise evolution of azole resistance through copy number variation followed by KSR1 loss of heterozygosity in Candida albicans
AU - Zande, Pétra Vande
AU - Gautier, Cécile
AU - Kawar, Nora
AU - Maufrais, Corinne
AU - Metzner, Katura
AU - Wash, Elizabeth
AU - Beach, Annette K.
AU - Bracken, Ryan
AU - Maciel, Eli Isael
AU - de Sá, Nívea Pereira
AU - Fernandes, Caroline Mota
AU - Solis, Norma V.
AU - Del Poeta, Maurizio
AU - Filler, Scott G.
AU - Berman, Judith
AU - Ene, Iuliana V.
AU - Selmecki, Anna
N1 - Publisher Copyright:
© 2024 Vande Zande et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2024/8
Y1 - 2024/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85202738878
U2 - 10.1371/journal.ppat.1012497
DO - 10.1371/journal.ppat.1012497
M3 - Article
C2 - 39213436
AN - SCOPUS:85202738878
SN - 1553-7366
VL - 20
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 8 August
M1 - e1012497
ER -