Sequencing, Disruption, and Characterization of the Candida albicans Sterol Methyltransferase ( ERG6 ) Gene: Drug Susceptibility Studies in erg6 Mutants
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The rise in the frequency of fungal infections and the increased resistance noted to the widely employed azole antifungals make the development of new antifungals imperative for human health. The sterol biosynthetic pathway has been exploited for the development of several antifungal agents (allylamines, morpholines, azoles), but additional potential sites for antifungal agent development are yet to be fully investigated. The sterol methyltransferase gene ( ERG6 ) catalyzes a biosynthetic step not found in humans and has been shown to result in several compromised phenotypes, most notably markedly increased permeability, when disrupted in Saccharomyces cerevisiae . The Candida albicans ERG6 gene was isolated by complementation of a S. cerevisiae erg6 mutant by using a C. albicans genomic library. Sequencing of the Candida ERG6 gene revealed high homology with the Saccharomyces version of ERG6 . The first copy of the Candida ERG6 gene was disrupted by transforming with the URA3 blaster system, and the second copy was disrupted by both URA3 blaster transformation and mitotic recombination. The resulting erg6 strains were shown to be hypersusceptible to a number of sterol synthesis and metabolic inhibitors, including terbinafine, tridemorph, fenpropiomorph, fluphenazine, cycloheximide, cerulenin, and brefeldin A. No increase in susceptibility to azoles was noted. Inhibitors of the ERG6 gene product would make the cell increasingly susceptible to antifungal agents as well as to new agents which normally would be excluded and would allow for clinical treatment at lower dosages. In addition, the availability of ERG6 would allow for its use as a screen for new antifungals targeted specifically to the sterol methyltransferase.
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ERG1, ERG7, ERG9, ERG25, ERG26, and ERG27 are essential, while ERG2, ERG3, ERG5, ERG6, and ERG24 are considered non-essential in ergosterol biosynthesis.
“By using the technology of gene disruption and controlled gene expression, ERG1 , ERG7 , ERG9 , ERG25 , ERG26 , and ERG27 have been proved to be essential, while ERG2 , ERG3 , ERG5 , ERG6 , and ERG24 are considered to be non-essential in ergosterol biosynthesis.”
From The synthesis, regulation, and functions of sterols in<i>Candida albicans</i>: Well-known but still lots to learn (2016) · cites this paper as [30]
The Discussion (page not provided) reports that viable C. albicans erg6 homozygotes demonstrate that ERG6 is not essential for viability. The paper does not establish the claimed essentiality classifications for ERG1, ERG7, ERG9, ERG25, ERG26, ERG27, ERG2, ERG3, ERG5, or ERG24. (LLM, conf=0.88)
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Self-citation
- Authors
- Jensen-Pergakes, K. L., Kennedy, M. A., Lees, N. D., Barbuch, R., Koegel, C., & Bard, M.
- Affiliations
- Indiana University – Purdue University Indianapolis (US)
- Hoechst Marion Roussel (United States) (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1998-05
- Volume
- 42
- Issue
- 5
- Pages
- 1160-1167
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC105764
- OpenAlex
- W2130745984
- Cited by
- 121
- References
- 38
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 9 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 10 · 2016: 8 · 2015: 4 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- 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 albicans, ERG6, sterol methyltransferase, sterol biosynthesis, ergosterol, antifungal susceptibility, azole resistance, terbinafine, tridemorph, fluphenazine, cycloheximide, cerulenin, brefeldin A, gene disruption, mitotic recombination, antifungal drug targets, Saccharomyces cerevisiae complementation
- MeSH terms
- Amino Acid Sequence, Antifungal Agents, Base Sequence, Candida albicans, Fungal Proteins, Genes, Fungal, Heterozygote, Methyltransferases, Microbial Sensitivity Tests, Molecular Sequence Data, Mutation, Sequence Alignment, Sequence Homology, Amino Acid
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