Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal

Arun Maji, Corinne P. Soutar, Jiabao Zhang, Agnieszka Lewandowska, Brice E. Uno, Su Yan, Yogesh Shelke, Ganesh Murhade, Evgeny Nimerovsky, Collin G. Borcik, Andres S. Arango, Justin D. Lange, Jonnathan P. Marin-Toledo, Yinghuan Lyu, Keith L. Bailey, Patrick J. Roady, Jordan T. Holler, Anuj Khandelwal, Anna M. SantaMaria, Hiram Sanchez, Praveen R. Juvvadi, Gina Johns, Michael J. Hageman, Joanna Krise, Teclegiorgis Gebremariam, Eman G. Youssef, Ken Bartizal, Kieren A. Marr, William J. Steinbach, Ashraf S. Ibrahim, Thomas F. Patterson, Nathan P. Wiederhold, David R. Andes, Taras V. Pogorelov, Charles D. Schwieters, Timothy M. Fan, Chad M. Rienstra () and Martin D. Burke ()
Additional contact information
Arun Maji: University of Illinois at Urbana-Champaign
Corinne P. Soutar: University of Illinois at Urbana-Champaign
Jiabao Zhang: University of Illinois at Urbana-Champaign
Agnieszka Lewandowska: University of Illinois at Urbana-Champaign
Brice E. Uno: University of Illinois at Urbana-Champaign
Su Yan: University of Illinois at Urbana-Champaign
Yogesh Shelke: University of Illinois at Urbana-Champaign
Ganesh Murhade: University of Illinois at Urbana-Champaign
Evgeny Nimerovsky: University of Illinois at Urbana-Champaign
Collin G. Borcik: Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign
Andres S. Arango: University of Illinois at Urbana-Champaign
Justin D. Lange: University of Illinois at Urbana-Champaign
Jonnathan P. Marin-Toledo: University of Illinois at Urbana-Champaign
Yinghuan Lyu: University of Illinois Urbana-Champaign
Keith L. Bailey: University of Illinois at Urbana-Champaign
Patrick J. Roady: University of Illinois at Urbana-Champaign
Jordan T. Holler: University of Illinois at Urbana-Champaign
Anuj Khandelwal: University of Illinois at Urbana-Champaign
Anna M. SantaMaria: University of Illinois at Urbana-Champaign
Hiram Sanchez: University of Wisconsin-Madison
Praveen R. Juvvadi: University of Arkansas for Medical Sciences
Gina Johns: Sfunga Therapeutics
Michael J. Hageman: The University of Kansas
Joanna Krise: The University of Kansas
Teclegiorgis Gebremariam: The Lundquist Institute
Eman G. Youssef: The Lundquist Institute
Ken Bartizal: Sfunga Therapeutics
Kieren A. Marr: Sfunga Therapeutics
William J. Steinbach: University of Arkansas for Medical Sciences
Ashraf S. Ibrahim: The Lundquist Institute
Thomas F. Patterson: University of Texas Health Science Center at San Antonio
Nathan P. Wiederhold: University of Texas Health Science Center at San Antonio
David R. Andes: University of Wisconsin-Madison
Taras V. Pogorelov: University of Illinois at Urbana-Champaign
Charles D. Schwieters: National Institutes of Health
Timothy M. Fan: University of Illinois at Urbana-Champaign
Chad M. Rienstra: University of Wisconsin-Madison
Martin D. Burke: University of Illinois at Urbana-Champaign

Nature, 2023, vol. 623, issue 7989, 1079-1085

Abstract: Abstract Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2–6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

Date: 2023
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DOI: 10.1038/s41586-023-06710-4

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