Molecular mechanisms of fluconazole resistance in Candida parapsilosis isolates from a U.S. surveillance system

Grossman, Nina T.; Pham, Cau D.; Cleveland, Angela A.; Lockhart, Shawn R.

doi:10.1128/aac.04613-14

Cited by 113Antifungal resistance and susceptibilityAntibiotic Resistance in BacteriaFungal Plant Pathogen Control

Molecular mechanisms of fluconazole resistance in Candida parapsilosis isolates from a U.S. surveillance system

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Grossman, Nina T., Pham, Cau D., Cleveland, Angela A., Lockhart, Shawn R.·2015·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.04613-14PMC PMC4335858

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Abstract

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 MRR1 and ERG11 (Y132F alone or with R398I), and overexpression of CDR1, MDR1, and ERG11.
“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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Wanamaker, E. B. (2013) · ProQuest Demo Repository
Candida parapsilosis İzolatlarında ERG11 ve MRR1 Direnç Genlerinin Araştırılması
Özge, K. U. R. T., Kuşkucu, M. A., YAZGAN, Z., Arslan, N., Aygün, G., & Küçükbasmacı, Ö. (2025) · Mikrobiyoloji Bulteni · doi:10.5578/mb.202503136

Authors: Grossman, N. T., Pham, C. D., Cleveland, A. A., & Lockhart, S. R.
Affiliations: Centers for Disease Control and Prevention (US)
ORCID: Grossman, Nina T.
Pham, Cau D.
Cleveland, Angela A.
Lockhart, Shawn R.
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
DOI: 10.1128/aac.04613-14
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
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › 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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Molecular mechanisms of fluconazole resistance in Candida parapsilosis isolates from a U.S. surveillance system

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