Since the FDA approval of Amphotericin B (AmB) in 1959, this polyene antifungal drug has become the primary treatment for systemic fungal infections due to its broad-spectrum antifungal activity and evasion of antimicrobial resistance1. However, the mortality rate for immunocompromised patients with systemic fungal infections remains high due to AmB’s toxicity1. Interaction with the fungal cell membrane sterol ergosterol is necessary for AmB’s antifungal activity2. Similarly, AmB’s toxicity is likely due to interaction with cholesterol in human cells. Although the importance of AmB’s interactions with cell membrane sterols has been well established, the nature of these interactions is poorly understood. Obtaining an atomic level understanding of antifungal-sterol interactions will inform the development of potent AmB derivatives with reduced toxicity. Here, we report highly precise AmB-sterol distance restraints obtained from REDOR experiments. Additionally, we have applied a previously reported3 paramagnetic relaxation enhancement assay for assessing AmB-sterol binding in the presence of POPC membranes to a series of mycopolyene drugs. The results support a shared mode of action among the mycopolyene family of antifungals.
1. Hamill, R. J. Amphotericin B formulations: A comparative review of efficacy and toxicity. Drugs 73, 919-934 (2013).
2. Gray, K. C., et al. Amphotericin primarily kills yeast by simply binding ergosterol. PNAS 109, 2234-2239 (2011).
3. Anderson, T. M. et al. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat. Chem. Biol. 10, 400–406 (2014).