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Molecular Mechanisms of Fluconazole Resistance in Candida parapsilosis Isolates from a U.S. Surveillance System
Open accessAbstract
Candida parapsilosis is the second or third most common cause of candidemia in many countries. The Infectious Diseases Society of America recommends fluconazole as the primary therapy for C. parapsilosis candidemia. Although the rate of fluconazole resistance among C. parapsilosis isolates is low in most U.S. institutions, the resistance rate can be as high as 7.5%. This study was designed to assess the mechanisms of fluconazole resistance in 706 incident bloodstream isolates from U.S. hospitals. We sequenced the ERG11 and MRR1 genes of 122 C. parapsilosis isolates with resistant (30 isolates; 4.2%), susceptible dose-dependent (37 isolates; 5.2%), and susceptible (55 isolates) fluconazole MIC values and used real-time PCR of RNA from 17 isolates to investigate the regulation of MDR1. By comparing these isolates to fully fluconazole-susceptible isolates, we detected at least two mechanisms of fluconazole resistance: an amino acid substitution in the 14-α-demethylase gene ERG11 and overexpression of the efflux pump MDR1, possibly due to point mutations in the MRR1 transcription factor that regulates MDR1. The ERG11 single nucleotide polymorphism (SNP) was found in 57% of the fluconazole-resistant isolates and in no susceptible isolates. The MRR1 SNPs were more difficult to characterize, as not all resulted in overexpression of MDR1 and not all MDR1 overexpression was associated with an SNP in MRR1. Further work to characterize the MRR1 SNPs and search for overexpression of other efflux pumps is needed.
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“Resistance to azoles in C. parapsilosis has been attributed to mutations in the transcription factor gene MRR1 [84] and ERG11 (Y132F, either alone or in combination with an R398I) [85,86,87], and overexpression of CDR1, MDR1, and ERG11 [85,86,88].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [87]
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Metadata
- Authors
- Grossman, N. T., Pham, C. D., Cleveland, A. A., & Lockhart, S. R.
- Affiliations
- Centers for Disease Control and Prevention (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2015-02
- Volume
- 59
- Issue
- 2
- Pages
- 1030-1037
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4335858
- OpenAlex
- W2099674708
- Cited by
- 112
- References
- 30
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 8 · 2023: 11 · 2022: 19 · 2021: 8 · 2020: 13 · 2019: 12 · 2018: 10 · 2017: 11 · 2016: 4 · 2015: 6
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Centers for Disease Control and Prevention
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Fungal Plant Pathogen Control
- Keywords
- Candida parapsilosis, fluconazole resistance, candidemia, ERG11, MRR1, single nucleotide polymorphisms, bloodstream isolates, resistance monitoring
- MeSH terms
- Antifungal Agents, Candida, Microbial Sensitivity Tests, Fluconazole, Gene Expression Regulation, Fungal, Drug Resistance, Fungal
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