A 5 + 1 polyene scaffold that selectively recognizes ergosterol's conjugated diene uncouples antifungal potency from host toxicity.

A 5+1 polyene scaffold in mandimycin M16 uncouples antifungal potency from host toxicity by selectively recognizing ergosterol's conjugated diene system.

• Why it matters: Current antifungal therapies like amphotericin B are limited by toxicity due to poor selectivity for fungal ergosterol over mammalian cholesterol, necessitating safer alternatives.
• What they did: Researchers engineered mandimycin M16 from a unique 5+1 polyene scaffold and tested its activity against 11 WHO priority fungal pathogens, assessing its selectivity and toxicity profiles.
• The result: M16 demonstrated potent broad-spectrum antifungal activity with no detectable cholesterol binding, hemolysis, or cytotoxicity up to 128 μg/mL in vitro and in mice, outperforming liposomal amphotericin B in infection models and achieving complete sterol selectivity.