Amphotericin has served as the gold standard for treatment of life-threatening systemic fungal infections for more than half a century, and resistance to this antibiotic remains exceptionally rare. However, amphotericin is also highly toxic, and thus the effective treatment of systemic fungal infections is all too often precluded, nt by a lack of efficacy, but by dose-limiting side effects. Because systemic fungal infections represent a major and growing threat to human health worldwide, a less toxic but equally effective amphotericin derivative stands to have a major impact. Recently, in contrast to the widely accepted channel model, we discovered that amphotericin primarily exerts its activity against yeast and human cells by simply binding ergosterol and cholesterol, respectively. Thus, rather than trying to promote the self-assembly of multimeric ion channels selectively in yeast vs. human cells, efforts toward an improved therapeutic index can now focus directly on the much simpler goal of more selectively binding ergosterol vs. cholesterol. To maximally enable the rational pursuit of this objective, we herein propose to harness the power of organic synthesis to systematically characterize the key structure-function relationships that underlie thi very rare type of small molecule-small molecule interaction. Collectively, these studies will substantially illuminate the fundamental underpinnings of AmB/sterol interactions that are central to the mechanism of action of this clinically vital antifungal agent, generate promising candidates for further development as antifungal agents with an improved therapeutic index, drive the continued development of a highly efficient and flexible building block-based platform for small molecule synthesis, as well as advance site-selective functionalizations as a powerful strategy for accessing targeted derivatives of complex natural products.

Public Health Relevance

Life-threatening fungal infections are a major problem in patients with a compromised immune system, including those undergoing chemotherapy, the elderly, and with AIDS. The best treatment currently available for these infections, amphotericin, is unfortunately also highly toxic. This proposal aims to reduce the toxicity while retaining the powerful antifungal activity of this clinically vital medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM080436-06
Application #
8505913
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2007-08-01
Project End
2017-01-31
Budget Start
2013-04-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$249,071
Indirect Cost
$39,071
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Li, Junqi; Ballmer, Steven G; Gillis, Eric P et al. (2015) Synthesis of many different types of organic small molecules using one automated process. Science 347:1221-6
Davis, Stephen A; Vincent, Benjamin M; Endo, Matthew M et al. (2015) Nontoxic antimicrobials that evade drug resistance. Nat Chem Biol 11:481-7
Cioffi, Alexander G; Hou, Jennifer; Grillo, Anthony S et al. (2015) Restored Physiology in Protein-Deficient Yeast by a Small Molecule Channel. J Am Chem Soc 137:10096-9
Li, Junqi; Grillo, Anthony S; Burke, Martin D (2015) From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks. Acc Chem Res 48:2297-307
Davis, Stephen A; Della Ripa, Lisa A; Hu, Lingbowei et al. (2015) C3-OH of Amphotericin B Plays an Important Role in Ion Conductance. J Am Chem Soc 137:15102-4
Anderson, Thomas M; Clay, Mary C; Cioffi, Alexander G et al. (2014) Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol 10:400-6
Woerly, Eric M; Roy, Jahnabi; Burke, Martin D (2014) Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat Chem 6:484-91
Woerly, Eric M; Miller, Jonathan E; Burke, Martin D (2013) (1-bromovinyl)-MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis. Tetrahedron 69:
Wilcock, Brandon C; Endo, Matthew M; Uno, Brice E et al. (2013) C2'-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells. J Am Chem Soc 135:8488-91
Wilcock, Brandon C; Uno, Brice E; Bromann, Gretchen L et al. (2012) Electronic tuning of site-selectivity. Nat Chem 4:996-1003

Showing the most recent 10 out of 17 publications