scholarly journals Persistent Candida albicans colonization and molecular mechanisms of azole resistance in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients

2010 ◽  
Vol 65 (12) ◽  
pp. 2505-2513 ◽  
Author(s):  
E. Siikala ◽  
R. Rautemaa ◽  
M. Richardson ◽  
H. Saxen ◽  
P. Bowyer ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Azole Resistance ◽  
Autoimmune Polyendocrinopathy

Molecular Mechanisms of Azole Resistance in Four Clinical Candida albicans Isolates

2021 ◽  
Author(s):  
Hongzhuo Shi ◽  
Yanli Zhang ◽  
Ming Zhang ◽  
Wenqiang Chang ◽  
Hongxiang Lou
Keyword(s):  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Azole Resistance

scholarly journals 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

2001 ◽  
Vol 45 (10) ◽  
pp. 2676-2684 ◽  
Author(s):  
Sofia Perea ◽  
José L. López-Ribot ◽  
William R. Kirkpatrick ◽  
Robert K. McAtee ◽  
Rebecca A. Santillán ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Azole Resistance ◽  
Mechanisms Of Resistance ◽  
Fluconazole Resistance ◽  
Immunodeficiency Virus ◽  
Genes Encoding ◽  
High Level ◽  
Target Enzyme

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 inC. 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.

scholarly journals Evaluation of Differential Gene Expression in Fluconazole-Susceptible and -Resistant Isolates of Candida albicans by cDNA Microarray Analysis

2002 ◽  
Vol 46 (11) ◽  
pp. 3412-3417 ◽  
Author(s):  
P. David Rogers ◽  
Katherine S. Barker
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Microarray Analysis ◽  
Molecular Mechanisms ◽  
Cell Stress ◽  
Differentially Expressed ◽  
Ergosterol Biosynthesis ◽  
Azole Resistance ◽  
Lipid Fatty Acid

ABSTRACT The opportunistic fungal pathogen Candida albicans is the major causative agent of oropharyngeal candidiasis (OPC) in AIDS. The development of azoles, such as fluconazole, for the treatment of OPC has proven effective except in cases where C. albicans develops resistance to fluconazole during the course of treatment. In the present study, we used microarray technology to examine differences in gene expression from a fluconazole-susceptible and a fluconazole-resistant well-characterized, clinically obtained matched set of C. albicans isolates to identify genes which are differentially expressed in association with azole resistance. Among genes found to be differentially expressed were those involved in amino acid and carbohydrate metabolism; cell stress, cell wall maintenance; lipid, fatty acid, and sterol metabolism; and small molecule transport. In addition to CDR1, which has previously been demonstrated to be associated with azole resistance, the drug resistance gene RTA3, the ergosterol biosynthesis gene ERG2, and the cell stress genes CRD2, GPX1, and IFD5 were found to be upregulated. Several genes, such as the mitochondrial aldehyde dehydrogenase gene ALD5, the glycosylphosphatidylinositol synthesis gene GPI1, and the iron transport genes FET34 and FTR2 were found to be downregulated. Further study of these differentially regulated genes is warranted to evaluate how they may be involved in azole resistance. In addition to these novel findings, we demonstrate the utility of microarray analysis for studying the molecular mechanisms of drug resistance in pathogenic organisms.

scholarly journals Candida albicans gains azole resistance by altering sphingolipid composition

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Jiaxin Gao ◽  
Haitao Wang ◽  
Zeyao Li ◽  
Ada Hang-Heng Wong ◽  
Yi-Zheng Wang ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Azole Resistance

scholarly journals Molecular mechanisms of azole resistance in Candida tropicalis isolates causing invasive candidiasis in China

2019 ◽  
Vol 25 (7) ◽  
pp. 885-891 ◽  
Author(s):  
X. Fan ◽  
M. Xiao ◽  
D. Zhang ◽  
J.-J. Huang ◽  
H. Wang ◽  
...  
Keyword(s):  
Candida Tropicalis ◽  
Invasive Candidiasis ◽  
Molecular Mechanisms ◽  
Azole Resistance

scholarly journals Candida Albicans ERG11 Gene Polymorphism: Impact on Its In Vivo Virulence and Susceptibility to Fluconazole According to the Galleria Mellonella Model

2021 ◽  
Author(s):  
Marcel Patindoilba Sawadogo ◽  
Adama Zida ◽  
Issiaka Soulama ◽  
Samuel S Sermé ◽  
Thierry Kiswendsida Guiguemdé ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Reference Strain ◽  
Galleria Mellonella ◽  
Larval Mortality ◽  
Fungal Burden ◽  
Significant Difference ◽  
Strain Sc5314 ◽  
Resistant Strains

The aim of this study is to have an idea on the molecular mechanisms of C. albicans resistance to fluconazole in Burkina Faso, by studying the polymorphism of the ERG11 gene, and its implication in the C. albicans virulence and resistance in vivo according to the Galleria mellonella model; (2) Methods: Ten (10) clinical strains including, 5 resistant and 5 susceptible and 1 virulent and susceptible reference strain SC5314 are used. For the estimation of virulence, the larvae were inoculated with 10 μL of C. albicans cell suspension at variable concentrations: 2,5.105, 5.105, 1.106, and 5.106 CFU/larva of each strain. For the in vivo efficacy study, fluconazole was administered at 1, 4 and 16 mg/kg respectively to G. mellonella larvae, after infection by inoculum 5.106 CFU / larvae of each strain; (3) Results: Six (6) non-silent mutations in the ERG11 gene (K143R, F145L, G307S, S405F, G448E, V456I on ERG11p) were found in 4 resistant isolates. Larval mortality depended on fungal burden and strain. The inoculum 5.106 CFU caused 100% mortality in 2 days for the 2 CAAL-1 and CAAL-2 strains carrying the F145L mutation, in 3 days for the reference strain SC5314, in 4 days for the ensemble of resistant strains, and in 5 days for the ensemble of susceptible strains. The comparison of the mortality due to the reference strain SC5314 CFU / larva and the average mortality due to the two mutant F145L strains, shows a significant difference (P <0.05).Fluconazole significantly protected (P> 0.05) the larvae from infection by susceptible strains and the reference strain. However, 100% mortality in 6 days after injection of the resistant strains, was observed (4) Conclusions: Certain mutations in the ERG11 gene such as the F145L mutation are thought to be a source of increased virulence in Candida albicans. Fluconazole effectively protected larvae from infection by susceptible strains in vivo, unlike resistant strain

Insights in the molecular mechanisms of an azole stress adapted laboratory-generated Aspergillus fumigatus strain

2021 ◽  
Author(s):  
Marion Aruanno ◽  
Samantha Gozel ◽  
Isabelle Mouyna ◽  
Josie E Parker ◽  
Daniel Bachmann ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Drug Transporters ◽  
Major Facilitator Superfamily ◽  
Ergosterol Biosynthesis ◽  
Azole Resistance ◽  
Drug Transporter

Abstract Aspergillus fumigatus is the main cause of invasive aspergillosis, for which azole drugs are the first-line therapy. Emergence of pan-azole resistance among A. fumigatus is concerning and has been mainly attributed to mutations in the target gene (cyp51A). However, azole resistance may also result from other mutations (hmg1, hapE) or other adaptive mechanisms. We performed microevolution experiment exposing an A. fumigatus azole-susceptible strain (Ku80) to sub-minimal inhibitory concentration of voriconazole to analyze emergence of azole resistance. We obtained a strain with pan-azole resistance (Ku80R), which was partially reversible after drug relief, and without mutations in cyp51A, hmg1, and hapE. Transcriptomic analyses revealed overexpression of the transcription factor asg1, several ATP-binding cassette (ABC) and major facilitator superfamily transporters and genes of the ergosterol biosynthesis pathway in Ku80R. Sterol analysis showed a significant decrease of the ergosterol mass under voriconazole exposure in Ku80, but not in Ku80R. However, the proportion of the sterol compounds was similar between both strains. To further assess the role of transporters, we used the ABC transporter inhibitor milbemycine oxime (MLB). MLB inhibited transporter activity in both Ku80 and Ku80R and demonstrated some potentiating effect on azole activity. Criteria for synergism were reached for MLB and posaconazole against Ku80. Finally, deletion of asg1 revealed some role of this transcription factor in controlling drug transporter expression, but had no impact on azole susceptibility. This work provides further insight in mechanisms of azole stress adaptation and suggests that drug transporters inhibition may represent a novel therapeutic target. Lay Summary A pan-azole-resistant strain was generated in vitro, in which drug transporter overexpression was a major trait. Analyses suggested a role of the transporter inhibitor milbemycin oxime in inhibiting drug transporters and potentiating azole activity.

scholarly journals Effects of Azole Antifungal Drugs on the Transition from Yeast Cells to Hyphae in Susceptible and Resistant Isolates of the Pathogenic Yeast Candida albicans

1999 ◽  
Vol 43 (4) ◽  
pp. 763-768 ◽  
Author(s):  
Kien C. Ha ◽  
Theodore C. White
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Opportunistic Infections ◽  
Antifungal Drugs ◽  
Yeast Cells ◽  
Pathogenic Yeast ◽  
Oral Infections ◽  
Antifungal Drug Resistance ◽  
Hyphal Formation

ABSTRACT Oral infections caused by the yeast Candida albicansare some of the most frequent and earliest opportunistic infections in human immunodeficiency virus-infected patients. The widespread use of azole antifungal drugs has led to the development of drug resistance, creating a major problem in the treatment of yeast infections in AIDS patients and other immunocompromised individuals. Several molecular mechanisms that contribute to drug resistance have been identified. InC. albicans, the ability to morphologically switch from yeast cells (blastospores) to filamentous forms (hyphae) is an important virulence factor which contributes to the dissemination ofCandida in host tissues and which promotes infection and invasion. A positive correlation between the level of antifungal drug resistance and the ability to form hyphae in the presence of azole drugs has been identified. Under hypha-inducing conditions in the presence of an azole drug, resistant clinical isolates form hyphae, while susceptible yeast isolates do not. This correlation is observed in a random sample from a population of susceptible and resistant isolates and is independent of the mechanisms of resistance.35S-methionine incorporation suggests that growth inhibition is not sufficient to explain the inhibition of hyphal formation, but it may contribute to this inhibition.

scholarly journals Multiple Molecular Mechanisms Contribute to a Stepwise Development of Fluconazole Resistance in Clinical Candida albicans Strains

1998 ◽  
Vol 42 (12) ◽  
pp. 3065-3072 ◽  
Author(s):  
Renate Franz ◽  
Steven L. Kelly ◽  
David C. Lamb ◽  
Diane E. Kelly ◽  
Markus Ruhnke ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Multiple Drug Resistance ◽  
Genetic Alterations ◽  
Mutant Form ◽  
Mrna Levels ◽  
Fluconazole Resistance ◽  
Stepwise Development ◽  
Target Enzyme

ABSTRACT From each of two AIDS patients with oropharyngeal candidiasis, fiveCandida albicans isolates from recurrent episodes of infection which became gradually resistant against fluconazole during antimycotic treatment were analyzed for molecular changes responsible for drug resistance. In both patients, a single C. albicans strain was responsible for the recurrent infections, but the CARE-2 fingerprint pattern of the isolates exhibited minor genetic alterations, indicating that microevolution of the strains took place during fluconazole therapy. In the isolates from patient 1, enhanced mRNA levels of theMDR1 gene, encoding a multiple drug resistance protein from the superfamily of major facilitators, and constitutive high expression of the ERG11 gene, coding for the drug target enzyme sterol 14α-demethylase, correlated with a stepwise development of fluconazole resistance. The resistant strains exhibited reduced accumulation of fluconazole and, for the last in the series, a slight increase in drug needed to inhibit sterol 14α-demethylation in vitro. In the isolates from patient 2, increasedMDR1 mRNA levels and the change from heterozygosity to homozygosity for a mutant form of the ERG11 gene correlated with continuously decreased drug susceptibility. In this series, reduced drug accumulation and increased resistance in the target enzyme activity, sterol 14α-demethylase, were observed. These results demonstrate that different molecular mechanisms contribute to a gradual development of fluconazole resistance in C. albicans.

scholarly journals Molecular mechanisms of azole resistance in Candida bloodstream isolates

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jocelyn Qi-Min Teo ◽  
Shannon Jing-Yi Lee ◽  
Ai-Ling Tan ◽  
Robyn Su-May Lim ◽  
Yiying Cai ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Azole Resistance
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