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Pécsvárad, Hungary

Virag E.,University of Pecs | Virag E.,PannonPharma Ltd. | Belagyi J.,University of Pecs | Gazdag Z.,University of Pecs | And 2 more authors.
Biochimica et Biophysica Acta - Biomembranes | Year: 2012

The direct interaction of the antibiotic primycin with the plasma membrane was investigated by employing the well-characterized ergosterol-producing, amphotericin B-sensitive parental Candida albicans strain 33erg + and its ergosterol-less amphotericin B-resistant plasma membrane mutant erg-2. The growth inhibition concentration in shaken liquid medium was 64 μg ml -1 for 33erg + and 128 μg ml -1 for erg-2, suggesting that the plasma membrane composition influences the mode of action of primycin. To determine the primycin-induced changes in the plasma membrane dynamic, electron paramagnetic resonance (EPR) spectroscopy methods were used, the spin-labeled fatty acid 5-(4,4-dimethyloxazolidine-N-oxyl)stearic acid) being applied for the in vivo measurements. The phase transition temperatures of untreated strain 33erg + and its mutant erg-2 were 12.5 °C and 11 °C, respectively. After 128 μg ml -1 primycin treatment, these values increased to 17.5 °C and 16 °C, revealing a significant reduction in the phospholipid flexibility. Saturation transfer EPR measurements demonstrated that, the rotational correlation times of the spin label molecule for the control samples of 33erg + and erg-2 were 60 ns and 100 ns. These correlation times gradually decreased on the addition of increasing primycin concentrations, reaching 8 μs and 1 μs. The results indicate the plasma membrane "rigidizing" effect of primycin, a feature that may stem from its ability to undergo complex formation with membrane constituent fatty acid molecules, causing alterations in the structures of phospholipids in the hydrophobic surface near the fatty acid chain region. © 2011 Elsevier B.V. All rights reserved.

Varga J.,University of Szeged | Kocinfe S.,University of Szeged | Peteri Z.,University of Szeged | Peteri Z.,PannonPharma Ltd. | And 2 more authors.
Toxins | Year: 2010

Ochratoxins are polyketide derived fungal secondary metabolites with nephrotoxic, immunosuppressive, teratogenic, and carcinogenic properties. Ochratoxin- producing fungi may contaminate agricultural products in the field (preharvest spoilage), during storage (postharvest spoilage), or during processing. Ochratoxin contamination of foods and feeds poses a serious health hazard to animals and humans. Several strategies have been investigated for lowering the ochratoxin content in agricultural products. These strategies can be classified into three main categories: prevention of ochratoxin contamination, decontamination or detoxification of foods contaminated with ochratoxins, and inhibition of the absorption of consumed ochratoxins in the gastrointestinal tract. This paper gives an overview of the strategies that are promising with regard to lowering the ochratoxin burden of animals and humans. © 2010 by the authors.

Nyilasi I.,University of Szeged | Nyilasi I.,PannonPharma Ltd. | Kocsube S.,University of Szeged | Kocsube S.,PannonPharma Ltd. | And 6 more authors.
Medical Mycology | Year: 2014

The investigation of the antifungal activities of drugs whose primary activities are not related to their antimicrobial potential is in the current forefront of research. Statin compounds, which are routinely used as cholesterol-lowering drugs, may also exert direct antimicrobial effects. In this study, the in vitro antifungal activities of various statins (lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin and pravastatin) were examined against one isolate each of four dermatophyte species (Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis and Microsporum gypseum). Basically, statins were effective in inhibiting all dermatophyte studied, but were particularly active against M. canis and T. mentagrophytes. Fluvastatin and simvastatin were active against all of the tested fungi causing a complete inhibition of their growth at very low concentrations (6.25-12.5 μg/ml). Lovastatin and rosuvastatin had inhibitory effects at higher concentrations (25-128 μg/ml), while atorvastatin and pravastatin proved the less effective. The in vitro interactions between statins and different antifungals (ketoconazole, itraconazole, fluconazole, amphotericin B, nystatin, griseofulvin, terbinafine and primycin) were also investigated using a standard chequerboard broth microdilution method. Synergetic interactions were observed in several cases, most of them were noticed when statins were combined with terbinafine and the different azoles. Some combinations were particularly active (ketoconazole-simvastatin or terbinafine-simvastatin), as they were found to exert synergistic effect against all of the investigated isolates. The other antifungals showed synergistic interactions with statins in only certain cases. These results suggest that statins exert substantial antifungal effects against dermatophyte fungi and they should be promising components in a combination therapy as they can act synergistically with a number of clinically used antifungal agents. © The International Society for Human and Animal Mycology 2013.

Nyilasi I.,University of Szeged | Nyilasi I.,PannonPharma Ltd. | Kocsube S.,University of Szeged | Kocsube S.,PannonPharma Ltd. | And 5 more authors.
FEMS Microbiology Letters | Year: 2010

The treatment of opportunistic fungal infections is often difficult as the number of available antifungal agents is limited. Nowadays, there is increasing interest in the investigation of the antifungal activity of nonantifungal drugs, and in the development of efficient antifungal combination therapy. In this study, the in vitro interactions of the effects of various statins (lovastatin, simvastatin, fluvastatin, atorvastatin (ATO), rosuvastatin (ROS) and pravastatin) and various azole antifungals [miconazole, ketoconazole, itraconazole and fluconazole (FLU)] against different opportunistic pathogenic fungi were investigated using a standard chequerboard broth microdilution method. When the investigated strains were sensitive to both compounds of the combination, additive interactions were frequently noticed. Synergistic interactions were observed in many cases when a strain was sensitive only to the azole compound (as in certain combinations with ATO or ROS) or the statin compound (as in certain combinations with FLU). In many combinations with an additive effect, the concentrations of drugs needed for total growth inhibition could be decreased by several dilution steps. Similar interactions were observed when the variability of the within-species sensitivities to some selected drug combinations was investigated. © 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Nyilasi I.,PannonPharma Ltd. | Nyilasi I.,University of Szeged | Kocsube S.,PannonPharma Ltd. | Kocsube S.,University of Szeged | And 4 more authors.
Journal of Medical Microbiology | Year: 2010

The in vitro antifungal activities of primycin (PN) and various statins against some opportunistic pathogenic fungi were investigated. PN completely inhibited the growth of Candida albicans (MIC 64 μg ml-1) and Candida glabrata (MIC 32 μg ml-1), and was very effective against Paecilomyces variotii (MIC 2 μg ml-1), but had little effect on Aspergillus fumigatus, Aspergillus flavus or Rhizopus oryzae (MICs >64 μg ml-1). The fungi exhibited different degrees of sensitivity to the statins; fluvastatin (FLV) and simvastatin (SIM) exerted potent antifungal activities against a wide variety of clinically important fungal pathogens. Atorvastatin, rosuvastatin and lovastatin (LOV) had a slight effect against all fungal isolates tested, whereas pravastatin was completely ineffective. The in vitro interactions between PN and the different statins were investigated using a standard chequerboard titration method. When PN was combined with FLV, LOV or SIM, both synergistic and additive effects were observed. The extent of inhibition was higher when these compounds were applied together, and the concentrations of PN and the given statin needed to block fungal growth completely could be decreased by several dilution steps. Similar interactions were observed when the variability of the within-species sensitivities was investigated. © 2010 SGM.

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