Amphotericin primarily kills yeast by simply binding ergosterol

TLDR

Amphotericin B is a natural product that forms ion channels in eukaryotic cells and is known to kill yeast primarily through channel‑mediated membrane permeabilization. Channel formation by Amphotericin B creates membrane pores that enhance potency and accelerate yeast killing. Amphotericin B’s fungicidal activity does not require channel formation; instead, it kills yeast by binding the essential lipid ergosterol, showing that channel activity is a secondary, separable mechanism.

Abstract

Amphotericin B (AmB) is a prototypical small molecule natural product that can form ion channels in living eukaryotic cells and has remained refractory to microbial resistance despite extensive clinical utilization in the treatment of life-threatening fungal infections for more than half a century. It is now widely accepted that AmB kills yeast primarily via channel-mediated membrane permeabilization. Enabled by the iterative cross-coupling-based synthesis of a functional group deficient derivative of this natural product, we have discovered that channel formation is not required for potent fungicidal activity. Alternatively, AmB primarily kills yeast by simply binding ergosterol, a lipid that is vital for many aspects of yeast cell physiology. Membrane permeabilization via channel formation represents a second complementary mechanism that further increases drug potency and the rate of yeast killing. Collectively, these findings ( i ) reveal that the binding of a physiologically important microbial lipid is a powerful and clinically validated antimicrobial strategy that may be inherently refractory to resistance, ( ii ) illuminate a more straightforward path to an improved therapeutic index for this clinically vital but also highly toxic antifungal agent, and ( iii ) suggest that the capacity for AmB to form protein-like ion channels might be separable from its cytocidal effects.