Electronic tuning of site selectivity and semisynthesis of C2'-deoxyamphotericin B
type: CreativeWork
description: The small molecule Amphotericin B (AmB) is a natural product that is utilized in the treatment of systemic fungal infections. AmB is effective against a broad spectrum of fungi, and resistance to this potent antifungal agent is rare. However, the use of AmB is limited due to its high toxicity. All of the details of the mechanism of AmB have not yet been elucidated, and a molecular understanding of the mechanisms and interactions of AmB would be an asset in the improvement of the therapeutic index of this antimycotic and in the development of other antimicrobials that would be refractory to resistance development. AmB is known to self-assemble into ion channels in phospholipid membranes containing sterol. The resulting membrane permeabilization has long been the leading hypothesis for the primary mechanism of antifungal activity. Three possible interactions involving the carboxylic acid and mycosamine appendages of AmB have been predicted to play important roles in the mechanism. To investigate the mode of action of AmB, derivatives of AmB lacking one or both of these appendages were synthesized and submitted to biophysical assays to determine their roles in the possible mechanistic interactions. It was found that the mycosamine was essential for antifungal activity, forming ion channels and mediating a direct interaction with ergosterol. The discovery that AmB directly binds ergosterol pointed to two possible primary mechanisms, membrane permeabilization through channel formation or ergosterol sequestration. The C35 hydroxyl group on AmB has been predicted to be important in the stabilization of the ion channel complex via hydrogen-bonding. A C35-deoxyAmB derivative was synthesized and evaluated for its antifungal activity, channel forming ability, and sterol binding capacity. C35-deoxyAmB was unable to permeablize yeast cells but still retained the ability to bind sterol and displayed significant antifungal activity. These findings support the conclusion that the p…
abstract: The small molecule Amphotericin B (AmB) is a natural product that is utilized in the treatment of systemic fungal infections. AmB is effective against a broad spectrum of fungi, and resistance to this potent antifungal agent is rare. However, the use of AmB is limited due to its high toxicity. All of the details of the mechanism of AmB have not yet been elucidated, and a molecular understanding of the mechanisms and interactions of AmB would be an asset in the improvement of the therapeutic index of this antimycotic and in the development of other antimicrobials that would be refractory to resistance development. AmB is known to self-assemble into ion channels in phospholipid membranes containing sterol. The resulting membrane permeabilization has long been the leading hypothesis for the primary mechanism of antifungal activity. Three possible interactions involving the carboxylic acid and mycosamine appendages of AmB have been predicted to play important roles in the mechanism. To investigate the mode of action of AmB, derivatives of AmB lacking one or both of these appendages were synthesized and submitted to biophysical assays to determine their roles in the possible mechanistic interactions. It was found that the mycosamine was essential for antifungal activity, forming ion channels and mediating a direct interaction with ergosterol. The discovery that AmB directly binds ergosterol pointed to two possible primary mechanisms, membrane permeabilization through channel formation or ergosterol sequestration. The C35 hydroxyl group on AmB has been predicted to be important in the stabilization of the ion channel complex via hydrogen-bonding. A C35-deoxyAmB derivative was synthesized and evaluated for its antifungal activity, channel forming ability, and sterol binding capacity. C35-deoxyAmB was unable to permeablize yeast cells but still retained the ability to bind sterol and displayed significant antifungal activity. These findings support the conclusion that the p…
author: Wilcock, Brandon
keywords: C2'-deoxyamphotericin B
date published: 2017-09-29T19:01:59Z
date modified: 2026-07-22T22:24:35Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/98443