Formation of Azole-Resistant Candida albicans by Mutation of Sterol 14-Demethylase P450
Open accessAbstract
The sterol 14-demethylase P450 (CYP51) of a fluconazole-resistant isolate of Candida albicans, DUMC136, showed reduced susceptibility to this azole but with little change in its catalytic activity. Twelve nucleotide substitutions, resulting in four amino acid changes, were identified in the DUMC136 CYP51 gene in comparison with a reported CYP51 sequence from a wild-type, fluconazole-susceptible C. albicans strain. Seven of these substitutions, including all of those causing amino acid changes, were located within a region covering one of the putative substrate recognition sites of the enzyme (SRS-1). Polymorphisms within this region were observed in several C. albicans isolates, and some were found to be CYP51 heterozygotes. Among the amino acid changes occurring in this region, only an alteration of Y132 was common among these fluconazole-resistant isolates, which suggests the importance of this residue to the fluconazole resistance of the target enzyme. DUMC136 and another fluconazole-resistant isolate were homozygotes with respect to CYP51, although the typical wild-type, fluconazole-susceptible C. albicans was a CYP51 heterozygote. These findings suggest that part of the fluconazole-resistant phenotype of C. albicans DUMC136 was acquired through a mutation-prone area of CYP51, an area which might promote the formation of fluconazole-resistant CYP51, along with a mechanism(s) which allows the formation of a homozygote of this altered CYP51 in this diploid pathogenic yeast.
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Increased activity or level of the enzymes of the ergosterol pathway (e.g., ERG11) reduces direct impact of the drug on its target.
“First, increased activity or level of the enzymes of the ergosterol pathway (e.g., ERG11) reduces direct impact of the drug on its target (Asai et al., 1999; Oliver et al., 2007).”
From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Asai et al., 1999
Previously identified mechanisms of fluconazole resistance are gain-of-function, resulting in increase in amount or activity level of Erg11 or efflux of drug transporters.
“whereas the previously identified mechanisms of fluconazole resistance are ‘gain of function’, resulting in the increase in the amount or activity level of Erg11 (Asai et al., 1999; Oliver et al., 2007) or the efflux of drug transporters (Coste et al., 2006; Dunkel et al., 2008).”
From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Asai et al., 1999
The genetic basis of major adaptive pathways in FLC-resistant C. albicans involves alterations or overexpression of ERG11 and upregulation of drug efflux pumps encoded by CDR1, CDR2, TAC1, MRR1, and MDR1.
“the genetic basis of major adaptive pathways have been identified: the first involves alterations or overexpression of ERG11, which produces the target demethylase”
From Acquisition of cross-azole tolerance and aneuploidy in <i>Candida albicans</i> strains evolved to posaconazole (2022) · cites this paper as Asai et al. 1999
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References 35 · Cited by 102
Research works printed but not linked: 1
- [3]Aoyama Y, Yoshida Y, Sato R. Yeast cytochrome P-450 catalyzing lanosterol 14α-demethylation. J Biol Chem. 1984;259:1661–1666. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/6420412/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Biol%20Chem&title=Yeast%20cytochrome%20P-450%20catalyzing%20lanosterol%2014%CE%B1-demethylation&author=Y%20Aoyama&author=Y%20Yoshida&author=R%20Sato&volume=259&publication_year=1984&pages=1661-1666&pmid=6420412&)]
- Authors
- Asai, K., Tsuchimori, N., Okonogi, K., Perfect, J. R., Gotoh, O., & Yoshida, Y.
- Affiliations
- Takeda (Japan) (JP)
- Duke University (US)
- Saitama Cancer Center (JP)
- Mukogawa Women's University (JP)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1999-05
- Volume
- 43
- Issue
- 5
- Pages
- 1163-1169
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC89127
- OpenAlex
- W1504969732
- Cited by
- 102
- References
- 35
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 2 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 2 · 2012: 2
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Candida albicans, fluconazole resistance, azole resistance, CYP51, cytochrome P450, point mutations, substrate recognition site, heterozygosity, diploid yeast, antifungal resistance
- MeSH terms
- Amino Acid Sequence, Antifungal Agents, Azoles, Candida albicans, Cytochrome P-450 Enzyme System, Drug Resistance, Microbial, Molecular Sequence Data, Mutation, Oxidoreductases, Gene Expression Regulation, Fungal, Sterol 14-Demethylase
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