Amphotericin primarily kills yeast by simply binding ergosterol.
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.
Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Kaitlyn C
KC
Gray
Daniel S
DS
Palacios
Ian
I
Dailey
Matthew M
MM
Endo
Brice E
BE
Uno
Brandon C
BC
Wilcock
Martin D
MD
Burke
D000666:Amphotericin B / Q000378:metabolism / Q000494:pharmacology*; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology*; D004875:Ergosterol / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects*
D000935:Antifungal Agents; D000666:Amphotericin B; D004875:Ergosterol