Affiliation:
1. Department of Medicine, Division of Infectious Diseases, The University of Texas Health Science Center at San Antonio,1 and
2. Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland2
3. Audie L. Murphy Division, South Texas Veterans Health Care System,3 San Antonio, Texas, and
Abstract
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, ≥64 μg/ml) isolated from human immunodeficiency virus (HIV)-infected patients with oropharyngeal candidiasis. The levels of expression of genes encoding lanosterol 14α-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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
390 articles.
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