Antifungal Activity of Compound 2d Against Dermatophytes via Ergosterol Pathway Disruption Original paper
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Karen 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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Microsporum canis (M. canis)
Microsporum canis (M. canis)
OverviewMicrosporum canis (M. canis) is a zoophilic dermatophyte common in cats and dogs, responsible for 90% of feline dermatophytoses worldwide.[1][2] It has significant zoonotic potential, transmitting to humans through fomites or direct animal contact, causing severe superficial mycosis. M. canis is considered anthropo-zoophilic and can infect pediatric or immunocompromised patients, causing severe inflammatory responses such […]
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Karen Pendergrass
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
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 evaluated the antifungal properties of potassium salts of N-acylhydrazinecarbodithioates (1a–e) and their aminotriazole-thione derivatives (2a–e) against keratinolytic fungi, including several dermatophytes. Given the rising resistance and toxicity concerns associated with conventional antifungals like terbinafine and azoles, the authors aimed to identify novel, less toxic alternatives with effective antidermatophytic activity. The compound 2d (5-amino-4-(naphthalene-1-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione) emerged as the most promising, showing activity against all tested fungal strains. Functional analyses using SEM, TEM, and RNA-seq were employed to explore its mechanism of action, including its impact on fungal morphology, transcriptomic profiles, and potential targets like ergosterol biosynthesis.
Who was studied?
The study used a panel of 14 keratinolytic fungal strains, including clinical and reference isolates of Trichophyton rubrum, T. interdigitale, T. tonsurans, T. granulosum, Microsporum canis, and Chrysosporium keratinophilum. Cytotoxicity was assessed using murine fibroblast (L929) and human epithelial (HeLa) cell lines, while transcriptomic effects were analyzed in T. rubrum CBS 120358. Control comparisons included antifungal agents amphotericin B and ketoconazole.
Most important findings
Compound 2d demonstrated broad-spectrum antifungal activity, with MIC values ranging from 32–128 mg/L against all tested strains. SEM and TEM showed that 2d inhibits mycelial growth and causes ultrastructural disruption in T. rubrum. RNA-seq analysis revealed 3,461 differentially expressed genes after 24 hours of 2d exposure, with downregulation of key genes in the ergosterol biosynthesis pathway (ERG3, ERG4, ERG6, ERG11, ERG25, ERG28), suggesting interference with membrane integrity. Additionally, oxidative stress-related genes (e.g., glutathione S-transferases, superoxide dismutases) were upregulated, indicating that 2d may induce ROS-mediated stress. Transmembrane transporter and cell wall-associated genes, including those encoding ABC and MFS efflux pumps and GPI-anchored proteins, were differentially regulated, suggesting disrupted detoxification and adherence processes.
Key implications
The findings position compound 2d as a promising antidermatophytic candidate with dual antifungal and low cytotoxicity profiles. Unlike traditional azoles, which often provoke compensatory ERG gene upregulation, 2d represses key ergosterol pathway genes, suggesting a distinct mechanism of action. Its ability to downregulate hydrophobin and GPI-anchor protein genes may enhance immune visibility of dermatophytes and impair host adherence. These properties, along with minimal mammalian toxicity and lack of broad-spectrum antibacterial activity, make 2d an ideal candidate for topical antifungal development. The study also illustrates how integrative RNA-seq analysis can elucidate the multifactorial responses of fungi to novel agents, aiding the identification of molecular targets for drug design.