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Dive into the research topics where Dominik Ausbacher is active.

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Featured researches published by Dominik Ausbacher.


Chemistry and Physics of Lipids | 2010

Liposome fractionation and size analysis by asymmetrical flow field-flow fractionation/multi-angle light scattering: influence of ionic strength and osmotic pressure of the carrier liquid.

Stefan Hupfeld; Helene H. Moen; Dominik Ausbacher; Heinrich Haas; Martin Brandl

Asymmetrical flow field-flow fractionation (AsFlFFF)/multi-angle light scattering (MALS) was employed for studying filter-extruded liposomes in carrier solutions with different ionic strength and osmolarity. By dilution of preformed liposome suspensions with different media, only the ionic strength in the external free aqueous phase was changed. Under such conditions the liposomes were found to elute at almost identical elution times, which is in contrast to earlier studies. This may be explained by two opposing effects: (a) modulation of inter-particulate and particle-wall-repulsion effects and (b) osmotic stress-induced changes in vesicle size. The latter effect was demonstrated when analysing liposomes upon dilution in media of constant ionic strength, but varying osmotic pressure (with or without 150mmolL(-1) sucrose supplement). The osmotic stress-induced change in liposome size was found to be size dependent. Larger liposomes appeared to both shrink and swell when exposed to hyper- or hypoosmotic media, respectively. Smaller liposomes appeared to shrink but not to swell. The potential causes of this effect are discussed.


Journal of Separation Science | 2009

Asymmetric flow field‐flow fractionation of liposomes: optimization of fractionation variables

Stefan Hupfeld; Dominik Ausbacher; Martin Brandl

The purpose of this study was to investigate the influence of ionic strength of the carrier liquid, cross flow rate, focus flow rate, and sample load on the retention behavior of liposomes in asymmetric flow field-flow fractionation (AF4). Two differently prepared samples of large unilamellar vesicles (LUV) were used. Experiments were performed varying the factors systematically and evaluating their effect on both retention behavior of the liposomes and on particle size as obtained from online coupled multi-angle light scattering (MALS) analysis. The results showed that the focus flow rate had the least influence on the elution of liposomes. Elution of LUV is mainly governed by the chosen cross flow condition and ionic strength of the carrier liquid as well as its sample load. Optimal fractionation and size analysis were achieved using a sample load of about 10 microg, a cross flow gradient from 1.0 to 0.1 mL/min over 35 min and a carrier solution of NaNO(3) with a concentration of 10 mM.


Journal of Medicinal Chemistry | 2011

Synthesis of Cationic Antimicrobial β2,2-Amino Acid Derivatives with Potential for Oral Administration

Terkel Hansen; Dominik Ausbacher; Gøril Eide Flaten; Martina Havelkova; Morten B. Strøm

We have prepared a series of highly potent achiral cationic β(2,2)-amino acid derivatives that fulfill the Lipinskis rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest β(2,2)-amino acid derivatives (M(w) 423.6) exhibiting a MIC of 3.8 μM against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 μM against Escherichia coli. The β(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the β(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.


Journal of Separation Science | 2009

Asymmetric flow field-flow fractionation of liposomes: 2. Concentration detection and adsorptive loss phenomena

Stefan Hupfeld; Dominik Ausbacher; Martin Brandl

The applicability of different concentration detection methods for online quantification of liposomes upon asymmetric flow field-flow fractionation was investigated. Filter-extruded egg phosphatidylcholine liposomes of different size were used. Online quantification using a differential refractive index (dRI) detector was found feasible for relatively high sample loads in the magnitude of 100 microg lipid (under the chosen fractionation conditions). UV-Vis detection of the turbidity of liposomes was ruled out as online detection method because turbidity increases with particle size and the signal is not only concentration but also particle-size dependent. Staining of liposomes by Rhodamine phosphatidylethanolamine or Sudan Red and subsequent online UV-Vis detection at the absorption maximum of the dye enabled quantification with much higher sensitivity than dRI detection. Furthermore analyte loss and carry-over phenomena upon repeated injection of varying liposome sample loads were studied using regenerated cellulose (RC) membranes as accumulation wall. It could be shown that RC membranes are prone to adsorption in case of very small sample loads (0.5 microg). This effect may be overcome by pre-saturation of the membrane with sample loads of at least 2 microg. For higher sample loads adsorptive losses play a minor role. Recovery from pre-saturated membranes reached approximately 100% and carry-over was found negligible.


Biochimica et Biophysica Acta | 2012

Anticancer mechanisms of action of two small amphipathic β(2,2)-amino acid derivatives derived from antimicrobial peptides.

Dominik Ausbacher; Gunbjørg Svineng; Terkel Hansen; Morten B. Strøm

We have recently discovered that small antimicrobial β(2,2)-amino acid derivatives (Mw<500) also display activity against cancer cells. To explore their drug potential, we have presently investigated the mechanisms of action of two derivatives BAA-1 (IC(50) 8.1μg/ml) and BAA-2 (IC(50) 3.8μg/ml) on Ramos human Burkitts lymphoma cells. Studies using annexin-V-FITC/propidium iodide staining and flow cytometry revealed essential mechanistic differences, which was confirmed by screening for active caspases, investigation of mitochondrial membrane potential, and electron microscopy studies. Our results indicated that BAA-1 killed Ramos cells by destabilizing the cell membrane, whereas BAA-2 caused apoptosis by the mitochondrial-mediated pathway.


Journal of Peptide Science | 2012

Synthesis of anticancer heptapeptides containing a unique lipophilic β2,2-amino acid building block

Veronika Tørfoss; Dominik Ausbacher; Cristiane de A. Cavalcanti-Jacobsen; Terkel Hansen; Bjørn-Olav Brandsdal; Martina Havelkova; Morten B. Strøm

We report a series of synthetic anticancer heptapeptides (H‐KKWβ2,2WKK‐NH2) containing eight different central lipophilic β2,2‐amino acid building blocks, which have demonstrated high efficiency when used as scaffolds in small cationic antimicrobial peptides and peptidomimetics. The most potent peptides in the present study had IC50 values of 9–23 µm against human Burkitts lymphoma and murine B‐cell lymphoma and were all nonhaemolytic (EC50 > 200 µm). The most promising peptide 10e also demonstrated low toxicity against human embryonic lung fibroblast cells and peripheral blood mononuclear cells and exceptional proteolytic stability. Copyright


Journal of Peptide Science | 2012

Improved anticancer potency by head‐to‐tail cyclization of short cationic anticancer peptides containing a lipophilic β2,2‐amino acid

Veronika Tørfoss; Johan Isaksson; Dominik Ausbacher; Bjørn-Olav Brandsdal; Gøril Eide Flaten; Trude Anderssen; Cristiane de A. Cavalcanti-Jacobsen; Martina Havelkova; Leonard T. Nguyen; Hans J. Vogel; Morten B. Strøm

We have recently reported a series of synthetic anticancer heptapeptides (H‐KKWβ2,2WKK‐NH2) containing a central achiral and lipophilic β2,2‐amino acid that display low toxicity against non‐malignant cells and high proteolytic stability. In the present study, we have further investigated the effects of increasing the rigidity and amphipathicity of two of our lead heptapeptides by preparing a series of seven to five residue cyclic peptides containing the two most promising β2,2‐amino acid derivatives as part of the central lipophilic core. The peptides were tested for anticancer activity against human Burkitts lymphoma (Ramos cells), haemolytic activity against human red blood cells (RBC) and cytotoxicity against healthy human lung fibroblast cells (MRC‐5). The results demonstrated a considerable increase in anticancer potency following head‐to‐tail peptide cyclization, especially for the shortest derivatives lacking a tryptophan residue. High‐resolution NMR studies and molecular dynamics simulations together with an annexin‐V‐FITC and propidium iodide fluorescent assay showed that the peptides had a membrane disruptive mode of action and that the more potent peptides penetrated deeper into the lipid bilayer. The need for new anticancer drugs with novel modes of action is demanding, and development of short cyclic anticancer peptides with an overall rigidified and amphipathic structure is a promising approach to new anticancer agents. Copyright


European Journal of Medicinal Chemistry | 2012

Anticancer activity of small amphipathic β2,2-amino acid derivatives

Terkel Hansen; Dominik Ausbacher; Zack G. Zachariassen; Trude Anderssen; Martina Havelkova; Morten B. Strøm

We report the anticancer activity from screening of a series of synthetic β(2,2)-amino acid derivatives that were prepared to confirm the pharmacophore model of short cationic antimicrobial peptides with high anti-Staphylococcal activity. The most potent derivatives against human Burkitts lymphoma (Ramos) cells displayed IC(50) values below 8 μM, and low toxicity against human red blood cells (EC(50) > 200 μM). A more than 5-fold preference for Ramos cancer cells compared to human lung fibroblasts (MRC-5 cells) was also obtained for the most promising β(2,2)-amino acid derivative 3-amino-N-(2-aminoethyl)-2,2-bis(naphthalen-2-ylmethyl)propanamide (5c). Screening of 5c at the National Cancer Institute (NCI, USA) confirmed its anticancer potency and revealed a very broad range of anticancer activity with IC(50) values of 0.32-3.89 μM against 59 different cancer cell lines. Highest potency was obtained against the colon cancer cell lines, a non-small cell lung cancer, a melanoma, and three leukemia cell lines included in the NCI screening panel. The reported β(2,2)-amino acid derivatives constitute a promising new class of anticancer agents based on their high anticancer potency, ease of synthesis, mode-of-action, and optimized pharmacokinetic properties compared to much larger antimicrobial peptides.


Biofouling | 2014

Staphylococcus aureus biofilm susceptibility to small and potent β2,2-amino acid derivatives

Dominik Ausbacher; Adyary Fallarero; Janni Kujala; Anni Määttänen; Jouko Peltonen; Morten B. Strøm; Pia Vuorela

Small antimicrobial β2,2-amino acid derivatives (Mw < 500 Da) are reported to display high antibacterial activity against suspended Gram-positive strains combined with low hemolytic activity. In the present study, the anti-biofilm activity of six β2,2-amino acid derivatives (A1–A6) against Staphylococcus aureus (ATCC 25923) was investigated. The derivatives displayed IC50 values between 5.4 and 42.8 μM for inhibition of biofilm formation, and concentrations between 22.4 and 38.4 μM had substantial effects on preformed biofilms. The lead derivative A2 showed high killing capacity (log R), and it caused distinct ultrastructural changes in the biofilms as shown by electron and atomic force microscopy. The anti-biofilm properties of A2 was preserved under high salinity conditions. Extended screening showed also high activity of A2 against Escherichia coli (XL1 Blue) biofilms. These advantageous features together with high activity against preformed biofilms make β2,2-amino acid derivatives a promising class of compounds for further development of anti-biofilm agents.


Journal of Peptide Science | 2014

Anticancer potency of small linear and cyclic tetrapeptides and pharmacokinetic investigations of peptide binding to human serum albumin

Annfrid Sivertsen; Veronika Tørfoss; Johan Isaksson; Dominik Ausbacher; Trude Anderssen; Bjørn-Olav Brandsdal; Martina Havelkova; Anne Elisabeth Skjørholm; Morten B. Strøm

We have in the present study explored the anticancer activity against human Burkitts lymphoma cells (Ramos) of a series of small linear and cyclic tetrapeptides containing a β2,2‐amino acid with either two 2‐naphthyl‐methylene or two para‐CF3‐benzyl side chains, along with their interaction with the main plasma protein human serum albumin (HSA). The cyclic and more amphipathic tetrapeptides revealed a notably higher anticancer potency against Ramos cells [50% inhibitory concentration (IC50) 11–70 μM] compared to the linear tetrapeptide counterparts (IC50 18.7 to >413 μM). The most potent cyclic tetrapeptide c3 had a 16.5‐fold preference for Ramos cells compared to human red blood cells, whereas the cyclic tetrapeptide c1 both showed low hemolytic activity and displayed the overall highest (2.9‐fold) preference for Ramos cells (IC50 23 μM) compared to healthy human lung fibroblast cells (MRC‐5). Investigating the interaction of selected tetrapeptides and recently reported hexapeptides with HSA revealed that the peptides bind to drug site II of HSA in the 22–28 μM range, disregarding size and overall structure. NMR and in silico molecular docking experiments identified the lipophilic residues as responsible for the interaction, but in vitro studies showed that the anticancer potency of the peptides varied in the presence of HSA and that c3 remained the most potent peptide. Based on our findings, we call for implementing serum albumin binding in development of anticancer peptides, as it may have implications for future administration and systemic distribution of peptide‐based cancer drugs. Copyright

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Martin Brandl

University of Southern Denmark

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