Microarray and Molecular Analyses of the Azole Resistance Mechanism in Candida glabrata Oropharyngeal Isolates

Tsai, Huei-Fung; Sammons, Lindsay R.; Zhang, Xiaozhen; Suffis, Sara D.; Su, Qin; Myers, Timothy G.; Marr, Kieren A.; Bennett, John E.

doi:10.1128/aac.00535-10

Cited by 80Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Microarray and Molecular Analyses of the Azole Resistance Mechanism in Candida glabrata Oropharyngeal Isolates

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Tsai, Huei-Fung, Sammons, Lindsay R., Zhang, Xiaozhen, Suffis, Sara D., Su, Qin, Myers, Timothy G., Marr, Kieren A., Bennett, John E.·2010·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.00535-10PMC PMC2916311

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Abstract

DNA microarrays were used to analyze Candida glabrata oropharyngeal isolates from seven hematopoietic stem cell transplant recipients whose isolates developed azole resistance while the recipients received fluconazole prophylaxis. Transcriptional profiling of the paired isolates revealed 19 genes upregulated in the majority of resistant isolates compared to their paired susceptible isolates. All seven resistant isolates had greater than 2-fold upregulation of C. glabrata PDR1 (CgPDR1), a master transcriptional regulator of the pleiotropic drug resistance (PDR) network, and all seven resistant isolates showed upregulation of known CgPDR1 target genes. The altered transcriptome can be explained in part by the observation that all seven resistant isolates had acquired a single nonsynonymous mutation in their CgPDR1 open reading frame. Four mutations occurred in the regulatory domain (L280P, L344S, G348A, and S391L) and one in the activation domain (G943S), while two mutations (N764I and R772I) occurred in an undefined region. Association of azole resistance and the CgPDR1 mutations was investigated in the same genetic background by introducing the CgPDR1 sequences from one sensitive isolate and five resistant isolates into a laboratory azole-hypersusceptible strain (Cgpdr1 strain) via integrative transformation. The Cgpdr1 strain was restored to wild-type fluconazole susceptibility when transformed with CgPDR1 from the susceptible isolate but became resistant when transformed with CgPDR1 from the resistant isolates. However, despite the identical genetic backgrounds, upregulation of CgPDR1 and CgPDR1 target genes varied between the five transformants, independent of the domain locations in which the mutations occurred. In summary, gain-of-function mutations in CgPDR1 contributed to the clinical azole resistance, but different mutations had various degrees of impact on the CgPDR1 target genes.

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The overlap between CandidaMine variants and two datasets of previously described drug resistance mutations (SENTRY database and PDR1 mutations from the literature) was low, comparable to that found in this work.
“In order to test this we calculated the overlap between CandidaMine variants and two datasets of previously described drug resistance-mutations: the SENTRY database6 and a set of described PDR1 mutations from the literature.71, 72, 73 This yielded low overlaps as well, comparable to those found in our work (Figure S5A).”
From Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata (2021) · cites this paper as [72]

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Authors: Tsai, H.-F., Sammons, L. R., Zhang, X., Suffis, S. D., Su, Q., Myers, T. G., Marr, K. A., & Bennett, J. E.
Affiliations: National Institutes of Health (US)
Johns Hopkins University (US)
ORCID: Zhang, Xiaozhen
Su, Qin
Myers, Timothy G.
Marr, Kieren A.
Bennett, John E.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2010-08
Volume: 54
Issue: 8
Pages: 3308-3317
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.00535-10
PMC: PMC2916311
OpenAlex: W2001393613
Cited by: 80
References: 31
Citations by year: 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 8 · 2018: 12 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 6 · 2013: 5 · 2012: 9
FWCI: 3.93
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: National Institutes of Health
National Institute of Allergy and Infectious Diseases
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: Candida glabrata, azole resistance, fluconazole resistance, PDR1, pleiotropic drug resistance, gene expression profiling, oropharyngeal candidiasis, hematopoietic stem cell transplant recipients, fluconazole prophylaxis, gain-of-function mutations, transcription factors, drug resistance mechanisms
MeSH terms: Antifungal Agents, Azoles, Candidiasis, Oral, DNA, Fungal, Fungal Proteins, Humans, Microbial Sensitivity Tests, Molecular Sequence Data, Mutation, Oropharynx, Fluconazole, Gene Expression Regulation, Fungal, Sequence Analysis, DNA, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Drug Resistance, Fungal, Candida glabrata

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Microarray and Molecular Analyses of the Azole Resistance Mechanism in Candida glabrata Oropharyngeal Isolates

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