Nectriatides with no antifungal activity bind to ergosterol and potentiate the antifungal activity of amphotericin B against Candida albicans

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The study investigated fungal cyclotetrapeptide nectriatide and its linear derivatives (nectriatide-based compounds) that themselves lack antifungal activity, but potentiate amphotericin B against Candida albicans. Using fluorescein- and biotin-tagged probes, microscopy showed probe localization at the fungal cell membrane, and membrane lipid binding assays found the highest affinity for the fungal sterol ergosterol with no affinity for cholesterol; ergosterol binding was supported by a liposome disruption assay. LC-MS quantification demonstrated that NCTs increased amphotericin B binding to C. albicans, and the authors attribute potentiation to NCT-driven ergosterol targeting that localizes amphotericin B and enhances its fungicidal effect. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Fungal cyclotetrapeptide nectriatide and its synthetic linear derivatives (nectriatide-based compounds, NCTs), having no antifungal activity, potentiated antifungal activity of amphotericin B (AmB) against Candida albicans . The mechanism of action was investigated using fluorescein-conjugated and biotin-tagged probes. Microscopy revealed fluorescent-probe localization at the C. albicans cell membrane. The biotinyl probe binding assay towards membrane lipids showed the highest affinity for ergosterol but no affinity for cholesterol. Ergosterol binding was confirmed by a liposome disruption assay. LC-MS quantification of AmB in C. albicans revealed that NCTs increased AmB binding to C. albicans . These results indicate that NCTs bind to ergosterol on the fungal plasma membrane, subsequently localizing AmB, explaining the observed potentiation of AmB fungicidal activity.
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Abstract Fungal cyclotetrapeptide nectriatide and its synthetic linear derivatives (nectriatide-based compounds, NCTs), having no antifungal activity, potentiated antifungal activity of amphotericin B (AmB) against Candida albicans. The mechanism of action was investigated using fluorescein-conjugated and biotin-tagged probes. Microscopy revealed fluorescent-probe localization at the C. albicans cell membrane. The biotinyl probe binding assay towards membrane lipids showed the highest affinity for ergosterol but no affinity for cholesterol. Ergosterol binding was confirmed by a liposome disruption assay. LC-MS quantification of AmB in C. albicans revealed that NCTs increased AmB binding to C. albicans. These results indicate that NCTs bind to ergosterol on the fungal plasma membrane, subsequently localizing AmB, explaining the observed potentiation of AmB fungicidal activity. Competing Interest Statement The authors have declared no competing interest.

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License: CC-BY-ND-4.0