Farnesol Boosts the Antifungal Effect of Fluconazole and Modulates Resistance in Candida auris through Regulation of the CDR1 and ERG11 Genes

Dekkerová, Jaroslava; Černáková, Lucia; Kendra, Samuel; Borghi, Elisa; Ottaviano, Emerenziana; Willinger, Birgit; Bujdáková, Helena

doi:10.3390/jof8080783

Cited by 11 publications

(10 citation statements)

References 49 publications

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“…Under physiological conditions, farnesol inhibits the yeast-to-hyphae transition, while tyrosol has the opposite effect in terms of morphogenesis (13,14). The observed potent inhibitory effect of these molecules at supraphysiological concentrations suggests that either farnesol or tyrosol may be a potential part of novel innovative preventive strategies against Candida biofilms, including against the C. auris sessile community as published previously (15)(16)(17)(18)(19). These studies showed that both molecules have a remarkable antifungal effect, interfering with redox homeostasis, virulence, and intracellular microelement contents against planktonic forms of C. auris; however, the transcriptome-based biofilm related changes remained to be elucidated (17,18,20).…”

Section: Introductionmentioning

confidence: 78%

Comparative transcriptional analysis ofCandida aurisbiofilms following farnesol and tyrosol treatment

Jakab,

Kovács,

Balla

et al. 2023

Preprint

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Candida aurisis frequently associated with biofilm-related invasive infections. The resistant profile of these biofilms necessitates innovative therapeutic options, where quorum sensing may be a potential target. Farnesol and tyrosol are two fungal quorum-sensing molecules with antifungal effects at supraphysiological concentrations. To date there has been no high-throughput comparative molecular analysis regarding the background of farnesol– or tyrosol-related effects againstC. aurisbiofilms. Here, we performed genome-wide transcript profiling withC. aurisbiofilms following 75 μM farnesol or 15 mM tyrosol exposure using transcriptome sequencing (RNA-Seq). The analysis highlighted that the number of up-regulated genes (a minimum 1.5-fold increase) was 686 and 138 for tyrosol and farnesol, respectively, while 662 and 199 genes were down-regulated (a minimum 1.5-fold decrease) for tyrosol and farnesol, respectively. The overlap between tyrosol– and farnesol-responsive genes was considerable (101 and 116 overlapping up-regulated and down-regulated genes, respectively). Genes involved in biofilm events, glycolysis, ergosterol biosynthesis, fatty acid oxidation, iron metabolism, and autophagy were primarily affected in treated cells. Farnesol caused an 89.9%, 73.8%, and 32.6% reduction in the calcium, magnesium, and iron content, respectively, whereas tyrosol resulted an 82.6%, 76.6%, and 81.2% decrease in the calcium, magnesium, and iron content compared to the control, respectively. Moreover, the complexation of farnesol, but not tyrosol, with ergosterol is impeded in the presence of exogenous ergosterol, resulting in a minimum inhibitory concentration increase in the quorum-sensing molecules. This study revealed several farnesol– and tyrosol-specific responses, which will contribute to the development of alternative therapies againstC. aurisbiofilms.ImportanceCandida aurisis a multidrug-resistant fungal pathogen, which is frequently associated with biofilm related infections.Candida-derived quorum-sensing molecules (farnesol and tyrosol) play a pivotal role in the regulation of fungal morphogenesis and biofilm development. Furthermore, they may have remarkable anti-biofilm effects, especially at supraphysiological concentrations. Innovative therapeutic approaches interfering with quorum-sensing may be a promising future strategy againstC. aurisbiofilms; however, limited data are currently available concerning farnesol-induced and tyrosol-related molecular effects inC. auris. Here, we detected several genes involved in biofilm events, glycolysis, ergosterol biosynthesis, fatty acid oxidation, iron metabolism, and autophagy, which were primarily influenced following farnesol or tyrosol exposure. Moreover, calcium, magnesium, and iron homeostasis were also significantly affected. These results reveal molecular events that provide definitive explanations for the observed anti-biofilm effect; furthermore, they support the development of novel therapeutic approaches againstC. aurisbiofilms.

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Section: Introductionmentioning

confidence: 78%

Comparative transcriptional analysis ofCandida aurisbiofilms following farnesol and tyrosol treatment

Jakab,

Kovács,

Balla

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Emerging antifungal compounds being investigated include natural compounds, antimicrobial peptides, immunotherapy, metals and nano particles, photodynamic and combinational therapy, and repurposed drugs [ 118 , 125 , 126 •, 127 ]. Colistin showed synergistic activity with amphotericin B against C. auris [ 128 ], while farnesol boosted the antifungal effect of fluconazole [ 129 ]. Fluconazole-resistant C. auris isolates have higher levels of chitin in their cell wall and increased susceptibility to a glucosamine-6-phosphate synthase inhibitor [ 130 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Strategies to Prevent Transmission of Candida auris in Healthcare Settings

Ahmad

Asadzadeh

2023

Curr Fungal Infect Rep

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Purpose of Review Candida auris , a recently recognized yeast pathogen, has become a major public health threat due to the problems associated with its accurate identification, intrinsic and acquired resistance to antifungal drugs, and its potential to easily contaminate the environment causing clonal outbreaks in healthcare facilities. These outbreaks are associated with high mortality rates particularly among older patients with multiple comorbidities under intensive care settings. The purpose of this review is to highlight strategies that are being adapted to prevent transmission of C. auris in healthcare settings. Recent Findings Colonized patients shed C. auris into their environment which contaminates surrounding equipment. It resists elimination even by robust decontamination procedures and is easily transmitted to new patients during close contact resulting in outbreaks. Efforts are being made to rapidly identify C. auris -infected/ C. auris -colonized patients, to determine its susceptibility to antifungals, and to perform effective cleaning and decontamination of the environment and isolation of colonized patients to prevent further transmission. Summary Rapid and accurate identification of hospitalized patients infected/colonized with C. auris , rapid detection of its susceptibility patterns, and appropriate use of infection control measures can help to contain the spread of this highly pathogenic yeast in healthcare settings and prevent/control outbreaks.

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“…Several non‐antifungal agents that demonstrated synergy with azoles against C. auris isolates are listed in Table 2, but, their specific synergistic mechanism, has yet to be discovered. Farnesol, a quorum‐sensing molecule, enhances the efficacy of fluconazole against C. auris by inhibiting the activity of CDR1 , and downregulating ERG11 [132]. Similarly, another study demonstrated that farnesol modulates C. albicans susceptibility to amphotericin B [133].…”

Section: Combination Therapies To Enhance Azole Efficacymentioning

confidence: 99%

Azole resistance in Candida auris: mechanisms and combinatorial therapy

Jangir,

Kalra,

Tanwar

et al. 2023

APMIS

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Multidrug resistance Candida auris is a dangerous fungal pathogen that is emerging at an alarming rate and posing serious threats to public health. C. auris is associated with nosocomial infections that cause invasive candidiasis in immunocompromised patients. Several antifungal drugs with distinct mechanisms of action are clinically approved for the treatment of fungal infections. The high rates of intrinsic and acquired drug resistance, particularly to azoles, reported in characterized clinical isolates of C. auris make treatment extremely problematic. In systemic infections, azoles are the first‐line treatment for most Candida species; however, the increasing use of drugs results in the frequent emergence of drug resistance. More than 90% of the clinical isolates of C. auris is shown to be highly resistant to azole drugs especially fluconazole, with some strains (types) resistant to all three classes of commonly used antifungals. This presents a huge challenge for researchers in terms of completely understanding the molecular mechanism of azole resistance to develop more efficient drugs. Due to the scarcity of C. auris therapeutic alternatives, the development of successful drug combinations provides an alternative for clinical therapy. Taking advantage of various action mechanisms, such drugs in combination with azole are likely to have synergistic effects, improving treatment efficacy and overcoming C. auris azole drug resistance. In this review, we outline the current state of understanding about the mechanisms of azole resistance mainly fluconazole, and the current advancement in therapeutic approaches such as drug combinations toward C. auris infections.

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Farnesol Boosts the Antifungal Effect of Fluconazole and Modulates Resistance in Candida auris through Regulation of the CDR1 and ERG11 Genes

Cited by 11 publications

References 49 publications

Comparative transcriptional analysis ofCandida aurisbiofilms following farnesol and tyrosol treatment

Comparative transcriptional analysis ofCandida aurisbiofilms following farnesol and tyrosol treatment

Strategies to Prevent Transmission of Candida auris in Healthcare Settings

Azole resistance in Candida auris: mechanisms and combinatorial therapy

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