Difference in virulence between fluconazole‐susceptible and fluconazole‐resistant <i>Candida albicans</i> in a mouse model

Schulz, Bettina; Weber, Kai; Schmidt, Axel; Zepelin, Margarete Borg-von; Ruhnke, Markus

doi:10.1111/j.1439-0507.2010.01970.x

Cited by 14 publications

(16 citation statements)

References 43 publications

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“…This is in contrast to the present study, where only neutral genetic markers were used for strain constructions. Another study concluded that a clinical isolate with high MDR1 mRNA levels exhibited decreased virulence (67). The finding of this study corroborated that of a separate one obtained with two fluconazole-resistant clinical isolates of C. albicans with MDR1 overexpression which exhibited low virulence in a murine model of systemic infection (25).…”

Section: Discussionsupporting

confidence: 84%

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Lohberger¹,

Coste²,

Sanglard³

2014

Eukaryot Cell

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Azoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur in Candida albicans principally by overexpression of multidrug transporter gene CDR1, CDR2, or MDR1 or by overexpression of ERG11, which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs) TAC1 (involved in the control of CDR1 and CDR2), MRR1 (involved in the control of MDR1), and UPC2 (involved in the control of ERG11). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial to C. albicans survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence of C. albicans in the absence of the selective drug pressure. In this work, the effect of GOF mutations on C. albicans virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neither TAC1 nor MRR1 GOF mutations had a significant effect on C. albicans virulence. In contrast, the presence of two hyperactive UPC2 alleles in C. albicans resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate with UPC2 hyperactive alleles was observed in competition experiments with the wild type in vivo but not in vitro. Interestingly, UPC2 hyperactivity delayed filamentation of C. albicans after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining the UPC2 GOF mutation with another hyperactive TF did not compensate for the negative effect of UPC2 on virulence. In conclusion, among the major TFs involved in azole resistance, only UPC2 had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.

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Section: Discussionsupporting

confidence: 84%

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Lohberger¹,

Coste²,

Sanglard³

2014

Eukaryot Cell

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“…Fluconazole-resistant C. albicans is responsible for most prevalent nosocomial fungal infections and has resulted in many clinical treatment failures in immunocompromised patients, leading to the search for novel antifungal agents urgent (Schulz et al 2011;Abdelmegeed and Shaaban 2013). KAE was considered a promising candidate to enhance the efficacy of traditional antifungal drug (such as FLC).…”

Section: Discussionmentioning

confidence: 99%

The roles of CDR1, CDR2, and MDR1 in kaempferol-induced suppression with fluconazole-resistant Candida albicans

Shao

Zhang

Wang

et al. 2015

Pharmaceutical Biology

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Context: Fungal infections caused by fluconazole-resistant Candida albicans are an intractable clinical problem, calling for new efficient antifungal drugs. Kaempferol, an active flavonoid, has been considered a potential candidate against Candida species. Objective: This work investigates the resistance reversion of kaempferol in fluconazole-resistant C. albicans and the underlying mechanism. Materials and methods: The antifungal activities of fluconazole and/or kaempferol were assessed by a series of standard procedures including broth microdilution method, checkerboard assay and time-kill (T-K) test in nine clinical strains as well as a standard reference isolate of C. albicans. Subsequently, the morphological changes, the efflux of rhodamine 6G, and the expressions of CDR 1, CDR 2, and MDR 1 were analysed by scanning electron microscope (SEM), inverted fluorescence microscope and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in C. albicans z2003.Results: For all the tested C. albicans strains, the minimum inhibitory concentrations (MICs) of fluconazole and kaempferol ranged 0.25-32 and 128-256 mg/mL with a range of fractional inhibitory concentration index of 0.257-0.531. In C. albicans z2003, the expression of both CDR 1 and CDR 2 were decreased after exposure to kaempferol alone with negligible rhodamine 6G accumulation, while the expression of CDR 1, CDR 2 and MDR 1 were all decreased when fluconazole and kaempferol were used concomitantly with notable fluorescence of rhodamine 6G observed. Discussion and conclusion: Kaempferol-induced reversion in fluconazole-resistant C. albicans might be likely due to the suppression of the expression of CDR1, CDR2 and MDR1.ARTICLE HISTORY

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“…Previously we demonstrated that rifampicin upregulated C. albicans MDR1 expression 24 . Co-induction of CSH1 and MDR1 has also been shown for a fluconazole-resistant C. albicans patient isolate 38 . Moreover, Mdr1 has been shown to be upregulated immediately after adhesion 39 , and both CSH1 (orf19.4477) and MDR1 (orf19.5604) transcription is mediated by the multidrug resistance regulator Mrr1p 40 .…”

Section: Discussionmentioning

confidence: 69%

Rifampicin induced virulence determinants increase Candida albicans biofilm formation

et al. 2013

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Discuss this article AbstractIncreased intravenous catheter use has been paralleled by increased bacterial and yeast bloodstream infection. Biofilm formation, which is associated with the cell surface hydrophobicity (CSH) phenotype, represents a major pathogenicity strategy of , becoming especially important in the colonization Candida albicans of intravascular medical devices. Increasing evidence shows the induction of virulence factors in by diverse substances. Therefore, we C. albicans investigated whether rifampicin, an antibiotic shown to be capable of inducing MDR1 expression in may also promote the formation of a C. albicans pathogenic biofilm. In response to 40 µg/mL rifampicin, an enhanced retention of SC5314 cells on polystyrene culture plates was observed by C. albicans measuring increased metabolic activity by XTT assay, indicating induction of biofilm formation. Rifampicin treatment also induced fibronectin binding, cell hydrophobicity and germ tube formation. Furthermore, increased RNA and protein expression of CSH1p, a major mediator of CSH, was demonstrated. We conclude that exposure to rifampicin may result in upregulation of key Candida virulence determinants, potentially boosting pathogenicity and supporting biofilm formation. This finding gains clinical significance from the increasing popularity of rifampicin-coated catheters, which might provide an advantageous gateway for bloodstream infections.

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Difference in virulence between fluconazole‐susceptible and fluconazole‐resistant Candida albicans in a mouse model

Cited by 14 publications

References 43 publications

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

The roles of CDR1, CDR2, and MDR1 in kaempferol-induced suppression with fluconazole-resistant Candida albicans

Rifampicin induced virulence determinants increase Candida albicans biofilm formation

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