Associations between Genomic Variants and Antifungal Susceptibilities in the Archived Global Candida auris Population
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Notice bibliographique
Résumé
Candida auris is a recently emerged human fungal pathogen that has posed a significant threat to public health. Since its first identification in 2009, this fungus has caused nosocomial infections in over 47 countries across all inhabited continents. As of May 2023, the whole-genome sequences of over 4000 strains have been reported and a diversity of mutations, including in genes known to be associated with drug resistance in other human fungal pathogens, have been described. Among them, 387 strains contained antifungal-susceptibility information for which different methods might be used depending on the drugs and/or investigators. In most reports on C. auris so far, the number of strains analyzed was very small, from one to a few dozen, and the statistical significance of the relationships between these genetic variants and their antifungal susceptibilities could not be assessed. In this study, we conducted genome-wide association studies on individual clades based on previously published C. auris isolates to investigate the statistical association between genomic variants and susceptibility differences to nine antifungal drugs belonging to four major drug categories: 5-fluorocytosine, amphotericin B, fluconazole, voriconazole, itraconazole, posaconazole, anidulafungin, caspofungin, and micafungin. Due to the small sample sizes for Clades II, V, and VI, this study only assessed Clades I, III, and IV. Our analyses revealed 15 single nucleotide polymorphisms (SNPs) in Clade I (10 in coding and 5 in noncoding regions), 24 SNPs in Clade III (11 in coding and 13 in noncoding regions), and 13 SNPs in clade IV (10 in coding and 3 in noncoding regions) as statistically significantly associated with susceptibility differences to one or more of the nine antifungal drugs. While four SNPs in genes encoding lanosterol 14-α-demethylase (ERG11) and the catalytic subunit of 1,3-beta-D-glucan synthase (FKS1) were shared between clades, including the experimentally confirmed Ser639Phe/Pro missense substitutions in FKS1 for echinocandin resistance, most of the identified SNPs were clade specific, consistent with their recent independent origins. Interestingly, the majority of the antifungal resistance-associated SNPs were novel, and in genes and intergenic regions that have never been reported before as associated with antifungal resistance. While targeted study is needed to confirm the role of each novel SNP, the diverse mechanisms of drug resistance in C. auris revealed here indicate both challenges for infection control and opportunities for the development of novel antifungal drugs against this and other human fungal pathogens.
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Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découle