Engineered polyene M16 distinguishes ergosterol from cholesterol, keeping antifungal activity while sparing host cells and kidneys in mice
- Mandimycin M16, built on a 5 + 1 polyene scaffold, was designed to overcome amphotericin B's poor discrimination between fungal and mammalian sterols.
- It recognizes the conjugated diene unique to ergosterol, shows no measurable cholesterol binding, and kills fungi rapidly across a panel of WHO priority pathogens.
- In vitro and in mice, hemolysis, cytotoxicity and kidney toxicity were undetectable at the doses tested.
- In disseminated infection models, it beat liposomal amphotericin B at matched doses, with large fungal burden reductions and full survival.
💡 Points
Undetectable nephrotoxicity sounds too clean for a polyene, and I'd want to know how long they dosed. Short mouse regimens rarely reproduce the cumulative tubular damage that limits amphotericin B over weeks in patients. Before taking M16 forward, I'd want repeat-dose tox with exposure data and a workable formulation; the cholesterol-sparing mechanism is convincing, but the safety margin is unproven.