The evolution of drug resistance in clinical isolates of Candida albicans.

Abstract

Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.

• Authors: Christopher B Ford, Jason M Funt, Darren Abbey, Luca Issi, Candace Guiducci, Diego A Martinez, Toni Delorey, Bi Yu Li, Theodore C White, Christina Cuomo, Reeta P Rao, Judith Berman, Dawn A Thompson, Aviv Regev
• Journal: eLife (Elife) Vol. 4 Pg. e00662 (Feb 03 2015) ISSN: 2050-084X [Electronic] England
• PMID: 25646566 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Fluconazole

Topics

• Adhesiveness
• Aneuploidy
• Candida albicans (drug effects, genetics, isolation & purification)
• Candidiasis (microbiology)
• Drug Resistance, Fungal (drug effects, genetics)
• Evolution, Molecular
• Fluconazole (pharmacology)
• Genetic Fitness (drug effects)
• Genome, Human
• Host-Pathogen Interactions (drug effects, genetics)
• Humans
• Loss of Heterozygosity (genetics)
• Microbial Sensitivity Tests
• Mutation (genetics)
• Phenotype
• Polymorphism, Single Nucleotide (genetics)
• Sequence Analysis, DNA
• Virulence (drug effects, genetics)