Fluconazole Downregulates Metallothionein in Microsporum canis and Increases Copper Toxicity Original paper
Researched by:
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Karen Pendergrass
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Karen Pendergrass
Read MoreKaren Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
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Microbes
Microbes
Microbes, short for microorganisms, are tiny living organisms that are ubiquitous in the environment, including on and inside the human body. They play a crucial role in human health and disease, functioning within complex ecosystems in various parts of the body, such as the skin, mouth, gut, and respiratory tract. The human microbiome, which is […]
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Karen Pendergrass
Read More
Researched by:
-
Karen Pendergrass
ID
Karen Pendergrass
Read More
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
What was studied?
This study investigated how fluconazole, an azole antifungal, affects the expression of the metallothionein (MT) gene in Microsporum canis (M. canis), a dermatophyte fungus responsible for zoonotic skin infections. While azoles are known to inhibit ergosterol synthesis, the researchers explored alternative, ergosterol-independent effects of fluconazole. Specifically, they isolated the MT gene from M. canis, characterized its structure and expression, and demonstrated that fluconazole rapidly downregulates both baseline and copper-induced MT expression. They also examined whether this downregulation increased fungal sensitivity to copper, thereby identifying MT repression as a potential antifungal mechanism. The focus of the study confirmed that fluconazole downregulates metallothionein in Microsporum canis, impacting its treatment approach.
Who was studied?
The subject of the study was Microsporum canis, an opportunistic dermatophyte pathogen that infects keratinized tissues of animals and humans. Clinical isolates of M. canis were cultured from patients at the University of Vienna Medical School. Experiments were conducted on fungal mycelia grown in vitro under various treatment conditions, including exposure to fluconazole, copper sulfate, and their combination.
Most important findings
The researchers identified and sequenced the metallothionein (MT) gene of Microsporum canis, revealing that it encodes a 23-amino acid protein containing 30% cysteine, arranged in the characteristic cys-x-cys motif found in metallothioneins. They discovered that fluconazole rapidly downregulates MT mRNA expression within 30 minutes of exposure, indicating an effect independent of its known inhibition of ergosterol synthesis. In contrast, copper (Cu²⁺) exposure induced MT expression within 15 minutes, peaking at one hour and remaining elevated for 24 hours.
When both fluconazole and copper were applied simultaneously, fluconazole suppressed the copper-induced MT upregulation, with marked inhibition by 24 hours. Functionally, the antifungal effect of copper at low concentrations (0.1–1 mM) was significantly amplified by fluconazole, while at high concentrations (10 mM), copper alone was sufficient to inhibit growth. These findings suggest that fluconazole disrupts the copper detoxification capacity of M. canis by downregulating MT, thereby increasing the fungus’s susceptibility to copper-induced oxidative damage.
Key implications
These findings broaden the mechanistic understanding of azole antifungals. Beyond inhibiting ergosterol synthesis, fluconazole can interfere with metal homeostasis by downregulating metallothioneins. This identifies MT as a novel, drug-responsive vulnerability in M. canis that could be exploited to enhance antifungal efficacy. Combination therapies using fluconazole with copper-based treatments—or interventions that inhibit fungal MT expression—may potentiate antifungal outcomes. Additionally, this study offers the first characterization of metallothionein in dermatophytes, positioning MT as a promising target for antifungal drug development, particularly in fluconazole-resistant infections.