The pore-forming action of polyenes: From model membranes to living organisms

Kristanc, Luka; Božić, Bojan; Jokhadar, Špela Zemljič; Dolenc, Marija Sollner; Gomišček, Gregor

doi:10.1016/j.bbamem.2018.11.006

Cited by 56 publications

(42 citation statements)

References 151 publications

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“…Permeable nonelectrolytes, such as glucose and smaller molecules, did not affect the cell lysis, whereas sucrose and maltose effectively protected cells from hemolysis (Figure 1D). The half‐maximal protection was observed at the size of molecules of 0.42 nm, which is close to the reported size of the nystatin pore 30,31 …”

Section: Resultssupporting

confidence: 84%

“…As a positive control for colloid osmotic RBC lysis, we used a polyenic antibiotic, nystatin, which forms water‐filled pores permeable for small inorganic cations and anions 30 . When applied at 200 µmol/L, nystatin completely lysed RBC.…”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, gossypol, as an amphiphilic molecule, could exert a direct detergent‐like solubilizing effect on plasmalemma. As a positive control for colloid osmotic RBC lysis, we used a polyenic antibiotic, nystatin, which forms water‐filled pores permeable for small inorganic cations and anions 30 . The nystatin‐induced haemolysis was fully blocked by non‐permeant carbohydrates in a size‐dependent manner consistent with the published size of the nystatin pore.Being lytic at high doses, gossypol, unexpectedly, protected cells at sublytic concentrations of 1–10 μmol/L (decreased Π 50% values in Figure 2B), possibly, due to physical intercalation of gossypol into lipid bilayer matrix 39 of the erythrocytes plasmalemma that may result in more dense packaging of the lipids.…”

Section: Discussionmentioning

confidence: 97%

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Lytic and sublytic effects of gossypol on red blood cells and thymocytes

Chorieva

Fayziev

Tsiferova

et al. 2020

Clin Exp Pharma Physio

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Gossypol is a natural polyphenol presently considered as a promising biological phytochemical with a range of activities including anticancer. We examined volume regulation‐dependent effects of gossypol using erythrocytes and thymic lymphocytes. Gossypol effectively lysed human red blood cells (RBC) with a half‐maximal concentration of 67.4 ± 1.6 μmol/L and in a non‐colloid osmotic manner. Sublytic gossypol doses of 1–10 μmol/L significantly protected RBC from osmotic hemolysis, but potentiated their sensitivity to the colloid‐osmotic lysis induced by a pore‐former nystatin. When added to the thymocytes suspension, gossypol caused a strong depression of the ability of cells to restore their volume under hypoosmotic stress with a half‐maximal activity at 2.1 ± 0.3 μmol/L. Gossypol suppressed regulatory volume decrease under experimental conditions, when cationic permeability was controlled by gramicidin D, and volume recovery depended mainly on anionic conductance, suggesting that the polyphenol inhibits the swelling‐induced anion permeability. In direct patch‐clamp experiments, gossypol inhibited the volume‐sensitive outwardly rectifying (VSOR) chloride channel in thymocytes and in human HCT116 and HeLa cells, possibly by a mechanism when gossypol molecule with a radius close to the size of channel pore plugs into the narrowest portion of the native VSOR chloride channel. Micromolar gossypol suppressed proliferation of thymocytes, HCT116 and HeLa cells. VSOR blockage may represent new mechanism of anticancer activity of gossypol in addition to its action as a BH3‐mimetic.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

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Lytic and sublytic effects of gossypol on red blood cells and thymocytes

Chorieva

Fayziev

Tsiferova

et al. 2020

Clin Exp Pharma Physio

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“…[ 17 ] and Candida auris [ 18 ] might not always be successful, often due to intrinsic or acquired resistance [ 14 ]. Still, polyene resistance is rarer [ 13 , 19 , 20 ], and the relative decrease in susceptibility is smaller, compared to resistance to other drug antifungal classes such as azoles or echinocandins [ 21 , 22 ] (see Section 4 . Polyene Resistance).…”

Section: Strengths and Drawbacks Of Polyene Use In The Clinicmentioning

confidence: 99%

“…The most studied mechanism of action is the pore forming model (see Section 3.2 . Pore Forming Models) in which polyenes interact with ergosterol to form ion-leaking pores in the membrane [ 19 ]. Nevertheless, it has been shown that pore formation can also be established in the absence of sterols [ 31 ].…”

Section: Mode Of Action Of Polyene Antifungal Drugsmentioning

confidence: 99%

Amphotericin B and Other Polyenes—Discovery, Clinical Use, Mode of Action and Drug Resistance

Carolus

Pierson

Lagrou

et al. 2020

JoF

166

144

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Although polyenes were the first broad spectrum antifungal drugs on the market, after 70 years they are still the gold standard to treat a variety of fungal infections. Polyenes such as amphotericin B have a controversial image. They are the antifungal drug class with the broadest spectrum, resistance development is still relatively rare and fungicidal properties are extensive. Yet, they come with a significant host toxicity that limits their use. Relatively recently, the mode of action of polyenes has been revised, new mechanisms of drug resistance were discovered and emergent polyene resistant species such as Candida auris entered the picture. This review provides a short description of the history and clinical use of polyenes, and focusses on the ongoing debate concerning their mode of action, the diversity of resistance mechanisms discovered to date and the most recent trends in polyene resistance development.

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Microbes to Man: From Soils and the Depths to Drugs

Newman¹

2021

Burger's Medicinal Chemistry and Drug Discovery

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This article covers microbially sourced antibiotics and anticancer agents that have either been approved by regulatory agencies (US and EU), are awaiting approval or are generally in Phases I–Phase III (cancer) or Phase I–IV (antibiotics). Also included are discussions of compounds that have been “developed” by synthetic chemists using as their templates, materials originally from microbes. Included are discussions on developments with genetic analyses of as yet uncultured (perhaps unculturable in the case of some symbionts), including use of environmental DNA (eDNA) as routes to novel agents where the microbe is unknown, even “unknowable.” In addition, examples are given of how agents that are too toxic to act as pharmaceutical agents in their own right, have now become major components of novel treatments for cancer treatment by linking these “toxins” to monoclonal antibodies directed to particular epitopes on cancerous cells, thus delivering highly toxic and effective agents directly to the site(s) needed. Comments have also been made about the lack of new antimicrobials, in particular directed toward fungal infections and the ESKAPE pathogen series, where agents long out of use, are now acting as templates upon which to design novel potent compounds.

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The pore-forming action of polyenes: From model membranes to living organisms

Cited by 56 publications

References 151 publications

Lytic and sublytic effects of gossypol on red blood cells and thymocytes

Lytic and sublytic effects of gossypol on red blood cells and thymocytes

Amphotericin B and Other Polyenes—Discovery, Clinical Use, Mode of Action and Drug Resistance

Microbes to Man: From Soils and the Depths to Drugs

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