AmB kills fungi through the formation of large sponge-like aggregates that remove ergosterol from the cell membrane of fungi. However, Arun Maji and colleagues found that as well as removing ergosterol, AmB also removes cholesterol — a sterol that demonstrates similarities to ergosterol and is essential for normal functioning of the cell membrane — from the membranes of kidney cells. A series of investigations and structural analyses enabled the researchers to make structural modifications that eliminated the ability of AmB to bind cholesterol. The resulting derivative was thus renal sparing, but also showed lower antifungal potency than AmB owing to its slower extraction of ergosterol. A further structural modification produced a new compound, AM-2-19, that was renal sparing in mice and in primary human kidney cells and demonstrated potent antifungal activity. In vitro studies also suggested that AM-2-19 retains potency to drug-resistant fungal strains. Clinical trials will be necessary to demonstrate the therapeutic efficacy and safety of the new compound; however, the researchers say that the insights gained from their studies also provide a conceptual framework for the rational optimization of other antimicrobials.