Amphotericin B and Nystatin show different activities on sterol-free vesicles

Whyte, B.S.; Peterson, R.P.; Hartsel, Scott C.

doi:10.1016/0006-291x(89)91503-9

Cited by 26 publications

(23 citation statements)

References 17 publications

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“…In this regard, it is important that AmB also forms ion channels in sterol-free small liposomes (23), which have curvatures in the range predicted for locally curved nanoscale raft domains (24). It follows that nonaqueous channels can also be formed by AmB in the external monolayer leaflet of raft microdomains that have a higher membrane curvature.…”

Section: The Formation Of Amb Ion Channels In the Nonraft And Raft Mementioning

confidence: 99%

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

Cohen

2016

Antimicrob Agents Chemother

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Drug resistance studies have played an important role in the validation of antibiotic targets. In the case of the polyene antibiotic amphotericin B (AmB), such studies have demonstrated the essential role that depletion of ergosterol plays in the development of AmB-resistant (AmB-R) organisms. However, AmB-R strains also occur in fungi and parasitic protozoa that maintain a normal level of ergosterol at the plasma membrane. Here, I review evidence that shows not only that there is increased protection against the deleterious consequences of AmB-induced ion leakage across the membrane in these resistant pathogens but also that a set of events are activated that block the cell signaling responses that trigger the oxidative damage produced by the antibiotic. Such signaling events appear to be the consequence of a membrane-thinning effect that is exerted upon lipid-anchored Ras proteins by the aqueous pores formed by AmB. A similar membrane disturbance effect may also explain the activity of AmB on mammalian cells containing Toll-like receptors. These resistance mechanisms expand our current understanding of the role that the formation of AmB aqueous pores plays in triggering signal transduction responses in both pathogens and host immune cells.

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Section: The Formation Of Amb Ion Channels In the Nonraft And Raft Mementioning

confidence: 99%

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

Cohen

2016

Antimicrob Agents Chemother

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“…For example, fungal membranes containing ergosterol are more sensitive to some polyene antibiotics than cholesterol-containing animal cell membranes (as a general rule, the antifungal activity increases with the number of double bonds in the lactone ring), whereas 3T3 cells are more susceptible to amphotericin B than are HeLa cells [19]. The interaction of the polyenes with sterol-containing plasma membranes causes impairment of membrane function, resulting in loss of intracellular monovalent and divalent cations and small molecules [6,20]. This mechanism is not fully understood, but some molecular models proposed include formation of aqueous pores comprising a ring of 8 or 10 polyene molecules spanning the lipid bilayer and perturbations in the lipid bilayer resulting from interactions between different lipid domains [21,22].…”

Section: Resultsmentioning

confidence: 99%

“…For instance, the sensitivity increases with ergosterol content in Saccharomyces cere6isiae [4], whereas inactivation of the ion channels in the plasma membrane induced by the polyene antibiotics is due to free radical induced-peroxidation of the polyenes [5]. The interaction of polyene antibiotics with biomembranes results in loss of intracellular protons and small molecules [6]. Among the more than 100 polyene antibiotics that have been isolated and characterized to date, some, like amphotericin B, nystatin and so on, are used in the clinical treatment of systemic fungal infections [4,7], while several polyenes are used as fungicides in agriculture [8].…”

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confidence: 99%

Specific recombinogenic activity of a new polyene antibiotic

Vachkova

Kappas

Tyagunenko

et al. 1998

CMLS, Cell. Mol. Life Sci.

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A new antibiotic from Streptomyces sp., tetrapol A159, active against various fungi, a promising compound for the control of plant diseases, was studied for its genotoxic effects. It was produced at the Institute of Microbiological Preparations for Agriculture, Sofia, Bulgaria. The chemical was tested in three different test systems: a bacterial system, the Ames test for point mutations, the micronucleus test in bone marrow cells of rats for chromosomal aberrations and the fungal system of Aspergillus nidulans for mitotic recombination and aneuploidy. No increase in histidine revertants was observed in any of the TA100, TA98, TA1535 and TA1537 strains of Salmonella at concentrations ranging from 1 to 4000 mg/plate. The results were also negative in the micronucleus test of bone marrow cells at concentrations from 124 to 600 mg/kg b.w., whereas a statistically significant threefold increase of mitotic crossovers was found in Aspergillus, at concentrations from 0.5 to 2.5 mg/ml.

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“…Although its mode of action is not yet fully understood, the most important mechanism appears to be the selective and irreversible binding to sterols (ergosterol and cholesterol) in cell membranes, thereby forming transmembrane channels (2,8,15). Furthermore, AMB was shown to form stable complexes with membrane phospholipids (9,25,34), to perturbate the fluidity of membranes (1,17), and to have an effect on anion transport and membrane-bound enzymes (3,7,33).…”

Section: Fig 2 Treatment Of Metacestode Vesicles With Amb and Benzimentioning

confidence: 99%

Effect of Amphotericin B on Larval Growth of Echinococcus multilocularis

Reuter

Merkle

Brehm

et al. 2003

Antimicrob Agents Chemother

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Alveolar echinococcosis is caused by the parasitic cestode Echinococcus multilocularis. Benzimidazoles, namely, mebendazole and albendazole, are the only drugs available for the treatment of inoperable alveolar echinococcosis. At present, no therapeutic alternative is available for patients with progressive disease under treatment or for patients who are unable to tolerate the side effects of the benzimidazoles. In addition, benzimidazoles are only parasitostatic for E. multilocularis. Thus, new therapeutic options are of paramount importance. In the present study we examined the in vitro effect of amphotericin B on E. multilocularis larvae. E. multilocularis metacestodes grown in the peritoneal cavities of Mongolian gerbils were transferred into a culture system. Vesicles budded from the tissue blocks and increased in number and size during the first 5 weeks. After 6 weeks drugs were added and deleterious effects on the vesicles were observed macroscopically and microscopically. By use of this in vitro tissue culture model we demonstrated that amphotericin B effectively inhibits the growth of E. multilocularis metacestodes. This destructive effect was significantly more rapid with amphotericin B than with the benzimidazoles. Cyclic treatment was effective in suppressing parasite growth. However, amphotericin B appears to be parasitostatic for E. multilocularis larvae, and regrowth occurs even after extended periods. In summary, amphotericin B constitutes the first promising alternative for the treatment of alveolar echinococcosis in cases of intolerance or resistance to benzimidazoles. It holds promise as an effective treatment option for otherwise fatal courses of disease.The larval stage of Echinococcus multilocularis causes alveolar echinococcosis (AE), a parasitic disease primarily affecting the liver. Human AE is endemic in regions of Western and Central Europe, Eastern Europe, North America, and Asia. Untreated AE is fatal in over 90% of cases, and surgical resection is often incomplete due to the diffuse infiltration of nonresectable structures.Benzimidazole carbamate derivatives, namely, mebendazole (MBZ) and albendazole (ABZ), are the only drugs available for the treatment of human AE. A disadvantage of the benzimidazoles is the fact that these drugs are parasitostatic rather than parasitocidal for E. multilocularis (5,6,36). This implies that the parasite is not depleted and may resume growth after discontinuation of treatment. Thus, benzimidazoles must be taken life long for the treatment of AE. The overall success rate of benzimidazole treatment ranges between 55 and 97% (6,19,24,32). Failure may be due to severe side effects, such as liver toxicity, forcing a discontinuation of the medication (11). Another cause of failure is progressive disease, despite benzimidazole treatment, observed in up to 16% of cases (6).At present, no reliable chemotherapeutic alternative can be offered to patients who do not tolerate or do not respond to benzimidazoles. Thus, it has become evident that new chemotherapeut...

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Amphotericin B and Nystatin show different activities on sterol-free vesicles

Cited by 26 publications

References 17 publications

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

Specific recombinogenic activity of a new polyene antibiotic

Effect of Amphotericin B on Larval Growth of Echinococcus multilocularis

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