Amphotericin B as a Potential Probe of the Physical State of Vesicle Membranes

Stano, Pasquale; Heer, Dominik; Walde, Peter; Carreira, Erick M.

doi:10.1021/ol0487276

Cited by 24 publications

(13 citation statements)

References 26 publications

(13 reference statements)

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“…To elucidate whether MSC administration is able to suppress the function of lung DCs in vivo , a model was used in which sensitization to OVA occurs via the airways by endogenous mDCs (30). In the preceding experiments, mice were depleted of pDCs with anti-Gr-1 Abs and then primed with a single injection of 800 mg of LPS-low OVA.…”

Section: Resultsmentioning

confidence: 99%

Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function

Zeng

Wei

et al. 2015

Molecular Medicine Reports

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Mesenchymal stem cells (MSCs) have been investigated in the treatment of numerous autoimmune diseases. However, the immune properties of MSCs on the development of asthma have remained to be fully elucidated. Airway dendritic cells (DCs) have an important role in the pathogenesis of allergic asthma, and disrupting their function may be a novel therapeutic approach. The present study used a mouse model of asthma to demonstrate that transplantation of MSCs suppressed features of asthma by targeting the function of lung myeloid DCs. MSCs suppressed the maturation and migration of lung DCs to the mediastinal lymph nodes, and thereby reducing the allergen-specific T helper type 2 (Th2) response in the nodes. In addition, MSC-treated DCs were less potent in activating naive and effector Th2 cells and the capacity of producing chemokine (C-C motif) ligand 17 (CCL17) and CCL22, which are chemokines attracting Th2 cells, to the airways was reduced. These results supported that MSCs may be used as a potential treatment for asthma.

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Section: Resultsmentioning

confidence: 99%

Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function

Zeng

Wei

et al. 2015

Molecular Medicine Reports

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“…Moreover, considering the amount of transport proteins that were up-regulated by natamycin treatment in addition to those tested in our assays, we propose that natamycin is able to block virtually all transport processes in the plasma membrane of fungi. Answering the question of how natamycin changes the membrane properties starts with the premise that the antibiotic action is attributable to binding to ergosterol (7), thereby affecting the functional properties the sterol has on membrane proteins either via ergosterol-rich domains (17) or more directly by interfering with a direct ergosterol-protein interaction. The different oxygen functions of natamycin may play a role in the latter mechanism, as is also suggested for other polyenes (6,18).…”

Section: Discussionmentioning

confidence: 99%

Polyene antibiotic that inhibits membrane transport proteins

Welscher

Leeuwen

Kruijff

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains.

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“…This model has been invoked to rationalize observations that, although AmB is typically most potent in membranes that contain sterols, increasing quantities of cholesterol (21,22) or ergosterol (23) can actually decrease the capacity for AmB to promote membrane permeabilization. Further supporting this model, AmB can permeabilize some artificial membranes in the absence of sterols (24)(25)(26)(27)(28).…”

mentioning

confidence: 99%

“…1E) (11)(12)(13)(30)(31)(32)(33)(34)(35)(36)(37)). An often invoked alternative model states that indirect effects on global membrane properties, rather than any direct binding interactions, are responsible for the impacts of membrane sterols on the biological activity of AmB (21)(22)(23)(24)(25)(26)(27)(28)(29).…”

mentioning

confidence: 99%

“…The first hypothesis states that indirect differential preorganization of membranes caused by different sterols is responsible (21)(22)(23)(24)(25)(26)(27)(28)(29). This model has been invoked to rationalize observations that, although AmB is typically most potent in membranes that contain sterols, increasing quantities of cholesterol (21,22) or ergosterol (23) can actually decrease the capacity for AmB to promote membrane permeabilization.…”

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confidence: 99%

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Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

Palacios

Dailey

Siebert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

115

134

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Amphotericin B is the archetype for small molecules that form transmembrane ion channels. However, despite extensive study for more than five decades, even the most basic features of this channel structure and its contributions to the antifungal activities of this natural product have remained unclear. We herein report that a powerful series of functional group-deficient probes have revealed many key underpinnings of the ion channel and antifungal activities of amphotericin B. Specifically, in stark contrast to two leading models, polar interactions between mycosamine and carboxylic acid appendages on neighboring amphotericin B molecules are not required for ion channel formation, nor are these functional groups required for binding to phospholipid bilayers. Alternatively, consistent with a previously unconfirmed third hypothesis, the mycosamine sugar is strictly required for promoting a direct binding interaction between amphotericin B and ergosterol. The same is true for cholesterol. Synthetically deleting this appendage also completely abolishes ion channel and antifungal activities. All of these results are consistent with the conclusion that a mycosamine-mediated direct binding interaction between amphotericin B and ergosterol is required for both forming ion channels and killing yeast cells. The enhanced understanding of amphotericin B function derived from these synthesis-enabled studies has helped set the stage for the more effective harnessing of the remarkable ion channel-forming capacity of this prototypical small molecule natural product.

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Amphotericin B as a Potential Probe of the Physical State of Vesicle Membranes

Cited by 24 publications

References 26 publications

Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function

Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function

Polyene antibiotic that inhibits membrane transport proteins

Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

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