25-30 August 2019
Henry Ford Building
Europe/Berlin timezone

Crucial Interactions for Amphotericin B Sterol Specificity Revealed by SSNMR

Not scheduled
4h
Harnack House and Henry Ford Building

Harnack House and Henry Ford Building

Board: 617
Poster-Late-OnlineAbstracts Late-Breaking Posters

Speaker

Ms Corinne Price (University of Illinois Urbana-Champaign)

Description

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.

References:
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).

Primary authors

Ms Corinne Price (University of Illinois Urbana-Champaign) Dr Agnieska Lewandowska (University of Illinois Urbana-Champaign)

Co-authors

Dr Manali Ghosh (Purdue University) Dr Su Yan (University of Illinois Urbana-Champaign) Dr Arun Maji (University of Illinois Urbana-Champaign) Mr Zhang Jiabao (University of Illinois Urbana-Champaign) Dr Nimerovsky Evgeny (University of Illinois Urbana-Champaign) Prof. Martin Burke (University of Illinois Urbana-Champaign) Prof. Chad Rienstra (University of Illinois Urbana-Champaign)

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