17 research outputs found

    Bisphosphonic acids as effective inhibitors of Mycobacterium tuberculosis glutamine synthetase

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    Inhibition of glutamine synthetase (GS) is one of the most promising strategies for the discovery of novel drugs against tuberculosis. Forty-three bisphosphonic and bis-H-phosphinic acids of various scaffolds, bearing aromatic substituents, were screened against recombinant GS from Mycobacterium tuberculosis. Most of the studied compounds exhibited activities in micromolar range, with N-(3,5-dichlorophenyl)-2-aminoethylidenebisphoshonic acid, N-(3,5-difluorophenyl)-2-aminoethylidene-bisphoshonic acid and N-(3,4-dichlorophenyl)-1-hydroxy-1,1-ethanebisphosphonic acid showing the highest potency with kinetic parameters similar to the reference compound – L-methionine-S-sulfoximine. Moreover, these inhibitors were found to be much more effective against pathogen enzyme than against the human ortholog. Thus, with the bone-targeting properties of the bisphosphonate compounds in mind, this activity/selectivity profile makes these compounds attractive agents for the treatment of bone tuberculosis

    Lipidation of temporin-1CEb derivatives as a tool for activity improvement, pros and cons of the approach

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    The alarming raise of multi-drug resistance among human microbial pathogens makes the development of novel therapeutics a priority task. In contrast to conventional antibiotics, antimicrobial peptides (AMPs), besides evoking a broad spectrum of activity against microorganisms, could offer additional benefits, such as the ability to neutralize toxins, modulate inflammatory response, eradicate bacterial and fungal biofilms or prevent their development. The latter properties are of special interest, as most antibiotics available on the market have limited ability to diffuse through rigid structures of biofilms. Lipidation of AMPs is considered as an effective approach for enhancement of their antimicrobial potential and in vivo stability; however, it could also have undesired impact on selectivity, solubility or the aggregation state of the modified peptides. In the present work, we describe the results of structural modifications of compounds designed based on cationic antimicrobial peptides DK5 and CAR-PEG-DK5, derivatized at their N-terminal part with fatty acids with different lengths of carbon chain. The proposed modifications substantially improved antimicrobial properties of the final compounds and their effectiveness in inhibition of biofilm development as well as eradication of pre-formed 24 h old biofilms of Candida albicans and Staphylococcus aureus. The most active compounds (C5-DK5, C12-DK5 and C12-CAR-PEG-DK5) were also potent against multi-drug resistant Staphylococcus aureus USA300 strain and clinical isolates of Pseudomonas aeruginosa. Both experimental and in silico methods revealed strong correlation between the length of fatty acid attached to the peptides and their final membranolytic properties, tendency to self-assemble and cytotoxicity

    Synthesis and Evaluation of Biological Activity of Antimicrobial – Pro-Proliferative Peptide Conjugates

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    <div><p>Skin represents the largest organ of the human body and plays a crucial role in its protection from the negative impact of the outside environment, maintains its homeostasis, enables sensory interaction and thermoregulation. The traumatized skin tissue undergoes several phenotype switches due to progressive reoxygenation and release of cytokine and growth factors, that activate mechanisms of reparative processes. However, in case of wounds colonized with pathogenic microflora natural regenerative mechanisms become substantially impaired, that could lead to chronic inflammatory states with non-healing skin lesions. Herein, we present the initial results of our studies aimed at the design of bifunctional peptide-based compounds. The chemical approach, that was utilized in this work, was based on the conjugation of antimicrobial peptides with the peptides, that have potential pro-proliferative and/or cytoprotective activity towards human keratinocytes and fibroblasts, in order to obtain antimicrobials with reduced cytotoxicity or compounds that maintain both activities, i.e. inhibit bacterial or fungi growth and activate cell proliferation/migration in <i>in vitro</i> tests. As a result, we obtained a group of peptide conjugates that effectively inhibited the growth of selected bacterial and fungi strains and were able to stimulate proliferation and migration of keratinocytes and fibroblasts under their effective microbicidal concentrations.</p></div

    Effect of the peptides on HaCaT keratinocytes and fibroblasts cell migration in the <i>in vitro</i> scratch test.

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    <p>HaCaT cells and fibroblasts were grown in 6-well plates until the 100% confluence was reached, then cells were starved for the next 12 hours in DMEM without 10% FCS and scratched once vertically with a 200μL pipette tip. After being washed two times with sterile PBS, a fresh portion of DMEM medium was added and cells were treated with the tested peptides applied at their optimal doses (25 μg/mL). Migration was analyzed after 24 hours by means of Zeiss Observer D1 microscope, wounding areas were analyzed with AxioVision software and expressed as the percentage of the wound width in comparison to the control sample (cells incubated in DMEM without FCS). Control+ FCS corresponds to the sample with cells incubated in the medium containing 10% FCS and was treated as the additional positive control. Data represent the mean ± SD of three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control.</p

    Antimicrobial activity of the peptides.

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    <p><sup>a)</sup>NI—no inhibitory activity</p><p>Antimicrobial activity of the peptides.</p

    Stimulating effect of DAL-PEG-KSLW peptide on the migration of keratinocytes and fibroblasts after 24 hours of incubation.

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    <p>A—control probe for keratinocytes, B—migration of keratinocytes in the presence of the peptide (25 μg/mL), C—the control probe for fibroblasts, D- migration of fibroblasts in the presence of the peptide (25 μg/mL). HaCaT cells and fibroblasts were grown on the 6-well plates to confluence. Then cells were serum-starved for the next 12 hours. After that, the medium was changed and cells were stimulated with the tested peptides applied at concentration of 25 μg/mL. Incubation was continued for the next 24 hours, then cells were fixed, dyed with 0.05% of crystal violet and analyzed using Zeiss Observer D1 microscope.</p
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