The polyene antibiotic amphotericin B acts as a Ca2+ ionophore in sterol-containing liposomes

Ramos, H.; Murciano, A. Attias de; Cohen, Benjamin E.; Bolard, Jacques

doi:10.1016/0005-2736(89)90069-2

Cited by 40 publications

(19 citation statements)

References 11 publications

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“…The interaction between amphotericin B and ergosterol seems to be more favorable for pore formation than that between amphotericin B and cholesterol [38] . Cellular components like potassium and ATP are found to leak out through these pores.…”

Section: Discussionmentioning

confidence: 92%

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Modes of Action of the New Arylguanidine Abafungin beyond Interference with Ergosterol Biosynthesis and in vitro Activity against Medically Important Fungi

et al. 2008

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Background:In contrast to the increasing numbers of agents for the treatment of invasive fungal infections, discoveries of new antifungal agents with therapeutic value in dermatomycoses are reported only rarely. Methods: Abafungin (chemical abstracts service registry No. 129639-79/8) is the first member of a novel class of synthetic antifungal compounds, the arylguanidines. It was first synthesized at Bayer AG, Leverkusen, Germany, and its antifungal action was discovered during the screening of H₂-receptor antagonists based on the structure of famotidine. To obtain insight into its mode of action and antifungal activity, various tests were carried out with different fungal pathogensin vitro. Results: Abafungin was found to have potent antifungal activity. Furthermore, mode-of-action studies suggested that abafungin exerts its antifungal activity regardless of whether the pathogens are growing or in a resting state. One target of abafungin was found to be the inhibition of transmethylation at the C-24 position of the sterol side chain, catalyzed by the enzyme sterol-C-24-methyltransferase. A second action of abafungin seems to be a direct effect on the fungal cell membrane.Conclusion: The observed characteristics of abafungin indicate that abafungin might be a promising antifungal agent defining a new class of antimycotics.

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Section: Discussionmentioning

confidence: 92%

“…Concerning direct impairment of the cell membrane, polyene antimycotics like amphotericin B and nystatin are known to act by binding to sterol, especially to ergosterol, which then leads to their lethal effect by forming transmembrane pores [38] . Cellular components like potassium ions and ATP then leak out through these pores.…”

Section: Discussionmentioning

confidence: 99%

Modes of Action of the New Arylguanidine Abafungin beyond Interference with Ergosterol Biosynthesis and in vitro Activity against Medically Important Fungi

et al. 2008

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“…The low molecular weight of mefloquine probably precludes the possibility of its acting as a channel former. The general hypothesis that mefloquine is an ionophore should be readily testable in vitro, by monitoring the influx of calcium into Fluo-3 (or another calcium dye)-containing liposomes or vesicles (28). A mefloquine-induced elevation of intraliposomal Ca 2ϩ would confirm that the initiation of the ionophoric effects of the drug may be receptor independent.…”

Section: Discussionmentioning

confidence: 99%

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

Caridha

Yourick

Cabezas

et al. 2008

Antimicrob Agents Chemother

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In previous studies, we have shown that mefloquine disrupts calcium homeostasis in neurons by depletion of endoplasmic reticulum (ER) stores, followed by an influx of external calcium across the plasma membrane. In this study, we explore two hypotheses concerning the mechanism(s) of action of mefloquine. First, we investigated the possibility that mefloquine activates non-N-methyl-D-aspartic acid receptors and the inositol phosphate 3 (IP3) signaling cascade leading to ER calcium release. Second, we compared the disruptive effects of mefloquine on calcium homeostasis to those of ionomycin in neuronal and nonneuronal cells. Ionomycin is known to discharge the ER calcium store (through an undefined mechanism), which induces capacitative calcium entry (CCE). In radioligand binding assays, mefloquine showed no affinity for the known binding sites of several glutamate receptor subtypes. The pattern of neuroprotection induced by a panel of glutamate receptor antagonists was dissimilar to that of mefloquine. Both mefloquine and ionomycin exhibited doserelated and qualitatively similar disruptions of calcium homeostasis in both neurons and macrophages. The influx of external calcium was blocked by the inhibitors of CCE in a dose-related fashion. Both mefloquine and ionomycin upregulated the IP3 pathway in a manner that we interpret to be secondary to CCE. Collectively, these data suggest that mefloquine does not activate glutamate receptors and that it disrupts calcium homeostasis in mammalian cells in a manner similar to that of ionomycin.Mefloquine is an antimalarial with utility for chemoprophylaxis and treatment. The drug has been associated with adverse central nervous system (CNS) effects in a dose-related manner (reviewed in reference 14). As a consequence, its continued use in an otherwise healthy population for prophylaxis is controversial. The precise etiology of mefloquine-induced adverse effects is unknown. There is clinical evidence that P glycoprotein polymorphisms are associated with adverse neurological outcomes (1). Numerous putative CNS targets have been proposed (reviewed in reference 12) in either in vitro or ex vivo contexts. Recent studies in our laboratory demonstrated mefloquine induction of brain stem histopathology consistent with direct cellular neurotoxicity in rats (12) and disruption of neuronal calcium homeostasis in vitro (14). The latter effect involves discharge of the endoplasmic reticulum (ER) calcium store and induction of a subsequent influx of calcium into the cell from the extracellular space (14). Initially we suspected that this effect might occur as a consequence of the inhibition of the thapsigargin-sensitive sarcoplasmic reticulum/ER Ca 2ϩ -ATPase (SERCA), followed by subsequent triggering of capacitative calcium entry (CCE). However, in subsequent gene expression studies, we observed that mefloquine failed to induce the downstream stress responses typical of thapsigargininduced ER calcium depletion (13). These observations suggested either that the interaction of mefloquine ...

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“…Stimulation of Ca 2ϩ influx is a possible mechanism and has been observed in human monocytes (18). However, it is unclear whether Ca 2ϩ is directly transported since the AMB-induced channels in cholesterol-containing model membranes are not appreciably Ca 2ϩ permeant (10,16). Alternatively, monovalent cation permeation could lead to membrane polarization or depolarization, leading to a secondary release of Ca 2ϩ from internal stores or from stimulated outer membrane Ca 2ϩ channels.…”

Section: Discussionmentioning

confidence: 99%

Antibody Array-Generated Profiles of Cytokine Release from THP-1 Leukemic Monocytes Exposed to Different Amphotericin B Formulations

Turtinen¹,

Prall²,

Bremer³

et al. 2004

Antimicrob Agents Chemother

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Cytokine antibody arrays were used to establish the profiles of cytokine release from THP-1 monocytes exposed to different amphotericin B (AMB) drug delivery systems. Fungizone (FZ) and Amphotec (ABCD) caused the release of significantly more inflammatory molecules and the release of inflammatory molecules at higher levels than either AmBisome (L-AMB) or Abelcet (ABLC) after 6 h of treatment. Specifically, tumor necrosis factor alpha (TNF-␣), interleukin-8 (IL-8), GRO-(␣␤␥), monocyte chemoattractant protein-1 (MCP-1), RANTES, IL-10, and IL-6 were detected and semiquantified with a chemiluminscence imaging system. TNF-␣, IL-8, and MCP-1 were the most predominant; however, little if any TNF-␣ was present in ABLC-or L-AMB-treated cultures. The TNF-␣ and IL-8 levels determined by quantitative enzyme-linked immunosorbent assay correlated with the relative cytokine levels measured by using the antibody arrays. Although the viabilities of THP-l monocytes in all AMB-treated cultures were similar by trypan blue exclusion, the amount of lactic dehydrogenase released was significantly larger in FZ-and ABCD-treated cultures than in L-AMBand ABLC-treated cultures, indicating more membrane perturbations with those formulations. Membrane cation channel formation was also measured in model cholesterol-containing large unilamellar vesicles to directly assess the ion channel formation ability of the system. Only FZ and ABCD induced significant ion currents at concentrations less than 1.5 ؋ 10 ؊5 M. These results may help provide rationales for the immediate cytokine-mediated side effects observed with FZ and ABCD and the reduced side effects observed with L-AMB and ABLC.Amphotericin B (AMB) is a polyene antifungal antibiotic and for a number of years has been the "gold standard" for the treatment of systemic fungal infections. Three new lipid-based formulations, Abelcet (ABLC), Ambisome (L-AMB), and Amphotec (ABCD), have been developed in an attempt to obtain improved efficacies, therapeutic indices, and tolerabilities compared to those of the traditional AMB formulation, Fungizone (FZ). In clinical trials, improvements in renal tolerability were shown for all three lipid formulations; however, the levels of acute toxicity, including fever, chills, hypotension, and nausea, vary with each formulation (8, 23). L-AMB has been shown to promote the least adverse effects, while immediate reactions to ABCD are often as frequent and severe as those to FZ (23). Clinical toxicity has been associated with increases in plasma tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) levels during infusion of the drug (1), while in vitro studies with the human THP-1 monocytic cell line have further identified and characterized a number of proinflammatory cytokines that are induced and released following exposure to FZ (5,19,20). Because the clinical effects of the four AMB formulations are different, we hypothesized that each AMB formulation would produce a different cytokine profile. Using recently developed antibody arrays (13, 27) and t...

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The polyene antibiotic amphotericin B acts as a Ca2+ ionophore in sterol-containing liposomes

Cited by 40 publications

References 11 publications

Modes of Action of the New Arylguanidine Abafungin beyond Interference with Ergosterol Biosynthesis and in vitro Activity against Medically Important Fungi

Modes of Action of the New Arylguanidine Abafungin beyond Interference with Ergosterol Biosynthesis and in vitro Activity against Medically Important Fungi

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

Antibody Array-Generated Profiles of Cytokine Release from THP-1 Leukemic Monocytes Exposed to Different Amphotericin B Formulations

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