Histone Deacetylase Inhibitors Enhance Candida albicans Sensitivity to Azoles and Related Antifungals: Correlation with Reduction in CDR and ERG Upregulation

Smith, W. Lamar; Edlind, Thomas D.

doi:10.1128/aac.46.11.3532-3539.2002

Cited by 147Antifungal resistance and susceptibilityHistone Deacetylase Inhibitors ResearchFungal and yeast genetics research

Histone Deacetylase Inhibitors Enhance Candida albicans Sensitivity to Azoles and Related Antifungals: Correlation with Reduction in CDR and ERG Upregulation

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Smith, W. Lamar, Edlind, Thomas D.·2002·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.46.11.3532-3539.2002PMC PMC128736

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Abstract

Histone acetylation and deacetylation play important roles in eukaryotic gene regulation. Several histone deacetylase (HDA) inhibitors have been characterized, including trichostatin A (TSA), apicidin, and sodium butyrate. We tested their effects on Candida albicans in vitro growth, heat sensitivity, and germ tube formation; minimal effects were observed. However, there was a dramatic effect of TSA on C. albicans sensitivity to the azoles fluconazole, itraconazole, and miconazole. Similar effects were observed with other HDA inhibitors and with the antifungals terbinafine and fenpropimorph, which target, as do azoles, enzymes in the ergosterol biosynthetic pathway. In contrast, HDA inhibitors had minimal effect on the activities of amphotericin B, flucytosine, and echinocandin, which have unrelated targets. Specifically, addition of 3 μg of TSA/ml lowered the itraconazole MIC for five susceptible C. albicans isolates an average of 2.7-fold at 24 h, but this increased to >200-fold at 48 h. Thus, the primary effect of TSA was a reduction in azole trailing. TSA also enhanced itraconazole activity against Candida parapsilosis and Candida tropicalis but had no effect with four less related yeast species. To examine the molecular basis for these effects, we studied expression of ERG genes (encoding azole and terbinafine targets) and CDR/MDR1 genes (encoding multidrug transporters) in C. albicans cells treated with fluconazole or terbinafine with or without TSA. Both antifungals induced to various levels the expression of ERG1 , ERG11 , CDR1 , and CDR2 ; addition of TSA reduced this upregulation 50 to 100%. This most likely explains the inhibition of azole and terbinafine trailing by TSA and, more generally, provides evidence that trailing is mediated by upregulation of target enzymes and multidrug transporters.

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TSA and other related KDAC inhibitors were previously found to have minimal antifungal activity against C. albicans but to enhance the effect of azole compounds and to reduce resistance of azole-resistant strains.
“TSA and other related lysine deacetylase (KDAC) inhibitors were previously found to have minimal antifungal activity against C. albicans but to enhance the effect of azole compounds and to reduce resistance of azole-resistant strains (21, 35, 36).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [36]
In yeasts, TSA and other KDAC inhibitors demonstrated very modest antifungal activity, despite their potentiating effect on azoles.
“In yeasts, TSA and other KDAC inhibitors demonstrated very modest antifungal activity, despite their potentiating effect on azoles (21, 35, 36).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [36]

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Authors: Smith, W. L., & Edlind, T. D.
Affiliations: Drexel University (US)
Corresponding author: Edlind, Thomas D.
ORCID: Smith, W. Lamar
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2002-11
Volume: 46
Issue: 11
Pages: 3532-3539
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.46.11.3532-3539.2002
PMC: PMC128736
OpenAlex: W2148279109
Cited by: 147
References: 42
Citations by year: 2026: 9 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 7 · 2020: 7 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 9 · 2015: 8 · 2014: 11 · 2013: 2 · 2012: 6
FWCI: 2.67
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 (5r01ai046768-04)
National Institute of Allergy and Infectious Diseases (AI46768)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: histone deacetylase inhibitors, trichostatin A, Candida albicans, azole resistance, CDR1, CDR2, multidrug transporter, ERG1, ERG11, terbinafine, fluconazole, itraconazole, miconazole, ergosterol biosynthesis, Candida parapsilosis, Candida tropicalis, antifungal susceptibility
MeSH terms: Terbinafine, Amphotericin B, Antifungal Agents, Azoles, Candida albicans, DNA-Binding Proteins, Enzyme Inhibitors, Flucytosine, Fungal Proteins, Hydroxamic Acids, Microbial Sensitivity Tests, Naphthalenes, Sterols, Transcription Factors, Up-Regulation, Gene Expression Regulation, Fungal, Itraconazole, ATP-Binding Cassette Transporters, Membrane Transport Proteins, Histone Deacetylase Inhibitors

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Histone Deacetylase Inhibitors Enhance Candida albicans Sensitivity to Azoles and Related Antifungals: Correlation with Reduction in CDR and ERG Upregulation

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