Mode of Action of the Antimycotic Agent G2 Isolated from Alfalfa Roots

Polacheck, Itzhack; Levy, M.; Guizie, Miriam; Zehavi, Uri; Naim, Michael; Evron, Ruth

doi:10.1016/s0934-8840(11)80172-6

Cited by 16 publications

(9 citation statements)

References 11 publications

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“…and Cryptococcus neoformans (Lalitha and Venkataraman, 1991;Polacheck et al, 1991). For example, medicagenic acid 3-O-beta-dglucopyranoside, an antimycotic saponin from alfalfa root, formed stable complexes with ergosterol, causing lethal leakage of ions out of yeast cells (Polacheck et al, 1991). The present study clearly revealed the antifungal activity of the steroidal saponins.…”

Section: Discussionmentioning

confidence: 51%

“…This activity has been documented in a number of saponins, and the damaging effects have been shown against a variety of fungi, including Candida albicans, Saccharomyces cerevisiae, Trichodemta viride, Acremonium spp. and Cryptococcus neoformans (Lalitha and Venkataraman, 1991;Polacheck et al, 1991). For example, medicagenic acid 3-O-beta-dglucopyranoside, an antimycotic saponin from alfalfa root, formed stable complexes with ergosterol, causing lethal leakage of ions out of yeast cells (Polacheck et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

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Antifungal activities and action mechanisms of compounds from Tribulus terrestris L.

Zhang

Xu²,

Cao

et al. 2006

Journal of Ethnopharmacology

105

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Antifungal activities and action mechanisms of compounds from Tribulus terrestris L.

Zhang

Xu²,

Cao

et al. 2006

Journal of Ethnopharmacology

105

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“…K ؉ leakage test in C. albicans. K ϩ leakage was determined by atomic absorption spectroscopy as described previously (41).…”

Section: Methodsmentioning

confidence: 99%

Toxicity Mechanisms of Amphotericin B and Its Neutralization by Conjugation with Arabinogalactan

Kagan

Ickowicz

Shmuel

et al. 2012

Antimicrob Agents Chemother

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c Amphotericin B (AMB) is an effective antifungal agent. However, its therapeutic use is hampered by its toxicity, mainly due to channel formation across kidney cell membranes and the disruption of postendocytic trafficking. We previously described a safe injectable AMB-arabinogalactan (AG) conjugate with neutralized toxicity. Here we studied the mechanism of the toxicity of free AMB and its neutralization by conjugation with AG. AMB treatment of a kidney cell line modulated the trafficking of three receptors (C-X-C chemokine receptor type 4 [CXCR4], M1 receptor, and human transferrin receptor [hTfnR]) due to an increase in endosomal pH. Similar data were also obtained in yeast but with an increase in vacuolar pH and the perturbation of Hxt2-green fluorescent protein (GFP) trafficking. The conjugation of AMB with AG neutralized all elements of the toxic activity of AMB in mammalian but not in fungal cells. Based on these results, we provide an explanation of how the conjugation of AMB with AG neutralizes its toxicity in mammalian cells and add to the knowledge of the mechanism of action of free AMB in both fungal and mammalian cells. Opportunistic fungal infections have emerged as an important cause of morbidity and mortality in immunodeficient patients (34). Amphotericin B (AMB) is considered one of the most effective antifungal agents; it exhibits wide-spectrum activity against both filamentous and yeast-like fungi, its pharmacokinetic and pharmacodynamic profiles are superior to those of other antifungal agents, and it is fungicidal, in contrast to most azoles which are fungistatic (3,39,53). The fungicidal effect is important, since most patients suffering from invasive fungal infections are immunocompromised (34). However, the infusionrelated and cumulative toxicities, particularly nephrotoxicity (14,20,30), of AMB have resulted in reductions in the routine use of deoxycholate micellar AMB formulations and the development of less-toxic high-cost lipid AMB formulations (16,36). To develop a soluble, less-toxic, and less costly formulation, AMB has been conjugated with various soluble macromolecules (18,37,(47)(48)(49).We conjugated AMB with arabinogalactan (AG) (18), which significantly increased the water solubility of AMB, reduced its toxicity, and resulted in an efficacy similar to that of Fungizone (a deoxycholate micellar formulation) and AmBisome (a lipid-based formulation) (18). AMB-related toxicity is associated with the inductions of interleukin 1␤ (IL-1␤), tumor necrosis factor ␣ (TNF-␣), and apoptosis in organs. These effects were not observed with the AMB-AG conjugate (AMB-AGC), suggesting its potential as a safer formulation for therapeutic use (19). AG is an inexpensive natural product, and the conjugation reactions are performed at room temperature, revealing promise for a potentially low-cost drug. AMB penetrates the plasma membrane (PM) and interacts with its sterols to form transmembrane channels, resulting in the leakage of monovalent ions and metabolites, which leads to cell death (5,22,4...

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“…The brown gum obtained after evaporation of the combined organic phase (1.2 g) was subjected to chromatography on Sephadex LH-20 (eluting with CHCl 3 -MeOH, 1:1) (compound 1, 200 mg, 2%). 1 H NMR, 13 C NMR and 2D NMR spectra were recorded on a Bruker ARX-500 spectrometer. Mass spectra (MS) data were recorded on a Fisons Autospec-Q spectrometer.…”

Section: Extraction and Isolationmentioning

confidence: 99%

Antifungal effect and possible mode of activity of a compound from the marine sponge Dysidea herbacea

Sionov

Roth

Sandovsky-Losica

et al. 2005

Journal of Infection

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Mode of Action of the Antimycotic Agent G2 Isolated from Alfalfa Roots

Cited by 16 publications

References 11 publications

Antifungal activities and action mechanisms of compounds from Tribulus terrestris L.

Antifungal activities and action mechanisms of compounds from Tribulus terrestris L.

Toxicity Mechanisms of Amphotericin B and Its Neutralization by Conjugation with Arabinogalactan

Antifungal effect and possible mode of activity of a compound from the marine sponge Dysidea herbacea

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