Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients

Details

Serval ID
serval:BIB_9BB7C142F6C9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients
Journal
Antimicrobial Agents and Chemotherapy
Author(s)
Perea  S., Lopez-Ribot  J. L., Kirkpatrick  W. R., McAtee  R. K., Santillan  R. A., Martinez  M., Calabrese  D., Sanglard  D., Patterson  T. F.
ISSN
0066-4804 (Print)
Publication state
Published
Issued date
10/2001
Volume
45
Number
10
Pages
2676-84
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Oct
Abstract
Molecular mechanisms of azole resistance in Candida albicans, including alterations in the target enzyme and increased efflux of drug, have been described, but the epidemiology of the resistance mechanisms has not been established. We have investigated the molecular mechanisms of resistance to azoles in C. albicans strains displaying high-level fluconazole resistance (MICs, > or =64 microg/ml) isolated from human immunodeficiency virus (HIV)-infected patients with oropharyngeal candidiasis. The levels of expression of genes encoding lanosterol 14alpha-demethylase (ERG11) and efflux transporters (MDR1 and CDR) implicated in azole resistance were monitored in matched sets of susceptible and resistant isolates. In addition, ERG11 genes were amplified by PCR, and their nucleotide sequences were determined in order to detect point mutations with a possible effect in the affinity for azoles. The analysis confirmed the multifactorial nature of azole resistance and the prevalence of these mechanisms of resistance in C. albicans clinical isolates exhibiting frank fluconazole resistance, with a predominance of overexpression of genes encoding efflux pumps, detected in 85% of all resistant isolates, being found. Alterations in the target enzyme, including functional amino acid substitutions and overexpression of the gene that encodes the enzyme, were detected in 65 and 35% of the isolates, respectively. Overall, multiple mechanisms of resistance were combined in 75% of the isolates displaying high-level fluconazole resistance. These results may help in the development of new strategies to overcome the problem of resistance as well as new treatments for this condition.
Keywords
Antifungal Agents/*pharmacology Azoles/*pharmacology Candida albicans/*drug effects/enzymology/metabolism Cytochrome P-450 Enzyme System/genetics/metabolism DNA-Binding Proteins/metabolism Drug Resistance, Microbial/genetics Fluconazole/pharmacology Gene Frequency HIV Infections/*microbiology Humans Microbial Sensitivity Tests Mutation Oxidoreductases/genetics/metabolism P-Glycoprotein/metabolism *Proto-Oncogene Proteins Transcription Factors/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 15:40
Last modification date
20/08/2019 16:02
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