scholarly journals Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity

2020 ◽  
Author(s):  
Marco Drexelius ◽  
André Reinhardt ◽  
Joshua Grabeck ◽  
Tom Cronenberg ◽  
Frank Nitsche ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Mammalian Cells ◽  
Building Blocks ◽  
Physicochemical Characteristics ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Cell Penetrating Peptides ◽  
Bacterial Strains ◽  
Cell Penetrating ◽  
Promising Source

Multidrug resistant (MDR) bacteria have adapted to most clinical antibiotics and are a growing threat to human health. One promising type of candidates for the everlasting demand of new antibiotic compounds constitute antimicrobial peptides (AMPs). These peptides act against different types of microbes by permeabilizing pathogen cell membranes, whereas being harmless to mammalian cells. Contrarily, another class of membrane-active peptides, namely cell-penetrating peptides (CPPs), is known to translocate in eukaryotic cells without substantially affecting the cell membrane. Since CPPs and AMPs share several physicochemical characteristics, we hypothesized if we can rationally direct the activity of a CPP towards antimicrobial activity. Herein, we describe the screening of a synthetic library, based on the CPP sC18, including structure-based design to identify the active residues within a CPP sequence and to discover novel AMPs with high activity. Peptides with increased hydrophobicity were tested against various bacterial strains, and hits were further optimized leading to four generations of peptides, with the last also comprising fluorinated amino acid building blocks. Interestingly, beside strong antibacterial activities, we also detected activity in cancer cells, while non-cancerous cells remained unharmed. The results highlight our new candidates, particularly those from generation 4, as a valuable and promising source for the development of future therapeutics with antibacterial activity and beyond.

scholarly journals Antimicrobial activity of some novel 2-(2-iodophenylimino)-5-arylidenethiazolidin-4-one derivatives

2018 ◽  
Vol 11 (5) ◽  
pp. 405-412 ◽  
Author(s):  
Duy Toan Pham ◽  
Thi My Huong Vo ◽  
Phuong Truong ◽  
Phuoc Tinh Ho ◽  
Manh Quan Nguyen
Keyword(s):  
Antimicrobial Activity ◽  
Aldol Condensation ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Therapeutic Agents ◽  
Antifungal Drugs ◽  
Resistant Bacteria ◽  
Bacterial Strains ◽  
Synthetic Process ◽  
New Compounds

AbstractBackgroundInfectious diseases, especially those caused by multidrug-resistant bacteria, are becoming a serious problem worldwide because of the lack of effective therapeutic agents. Moreover, most antifungal drugs exhibit low efficacy and high toxicity because of the similarity between fungal and human cells. These issues warrant the search for potential new agents.ObjectivesTo synthesize potent 2-(2-iodophenylimino)-5-arylidenethiazolidin-4-one derivatives, improve the synthetic process, elucidate their structures, and determine their antimicrobial activity.Methods2-Iodoaniline was used as an initial reactant in a 3-step process for the synthesis of 2-(2-iodophenylimino)-5-arylidenethiazolidin-4-one derivatives, including an acylation reaction, a cyclization reaction, and aldol condensation reactions. The structures of the obtained derivatives were investigated and elucidated using spectral methods. Antimicrobial activity toward 5 bacterial strains and 2 fungal strains was determined using Kirby–Bauer and agar dilution methods.ResultsWe successfully synthesized 12 novel compounds and elucidated their structures. The derivatives had no antifungal activities. By contrast, they showed remarkable antibacterial activities. Some of them with minimum inhibitory concentrations (MICs) ≤8 μg/mL in both Staphylococcus aureus and methicillin-resistant S. aureus.ConclusionsA simple and flexible way to synthesize new compounds with a thiazolidin-4-one ring was determined. Some of these new compounds have outstanding effects with low MICs for bacteria. Their further investigation as therapeutic agents is warranted.

scholarly journals Antibacterial Activities of Amphiphilic Cyclic Cell-Penetrating Peptides against Multidrug-Resistant Pathogens

2014 ◽  
Vol 11 (10) ◽  
pp. 3528-3536 ◽  
Author(s):  
Donghoon Oh ◽  
Jiadong Sun ◽  
Amir Nasrolahi Shirazi ◽  
Kerry L. LaPlante ◽  
David C. Rowley ◽  
...  
Keyword(s):  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating ◽  
Multidrug Resistant Pathogens

scholarly journals Antimicrobial Activity of Cyclic-Monomeric and Dimeric Derivatives of the Snail-Derived Peptide Cm-p5 against Viral and Multidrug-Resistant Bacterial Strains

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 745
Author(s):  
Melaine González-García ◽  
Fidel Morales-Vicente ◽  
Erbio Díaz Pico ◽  
Hilda Garay ◽  
Daniel G. Rivera ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Activity ◽  
Antifungal Activity ◽  
Multidrug Resistant ◽  
Moderate Activity ◽  
Dependent Manner ◽  
Bacterial Strains ◽  
Acinetobacter Baumanii ◽  
Concentration Dependent Manner ◽  
Conventional Antibiotics

Cm-p5 is a snail-derived antimicrobial peptide, which demonstrated antifungal activity against the pathogenic strains of Candida albicans. Previously we synthetized a cyclic monomer as well as a parallel and an antiparallel dimer of Cm-p5 with improved antifungal activity. Considering the alarming increase of microbial resistance to conventional antibiotics, here we evaluated the antimicrobial activity of these derivatives against multiresistant and problematic bacteria and against important viral agents. The three peptides showed a moderate activity against Pseudomonas aeruginosa, Klebsiella pneumoniae Extended Spectrum β-Lactamase (ESBL), and Streptococcus agalactiae, with MIC values > 100 µg/mL. They exerted a considerable activity with MIC values between 25–50 µg/mL against Acinetobacter baumanii and Enterococcus faecium. In addition, the two dimers showed a moderate activity against Pseudomonas aeruginosa PA14. The three Cm-p5 derivatives inhibited a virulent extracellular strain of Mycobacterium tuberculosis, in a dose-dependent manner. Moreover, they inhibited Herpes Simplex Virus 2 (HSV-2) infection in a concentration-dependent manner, but had no effect on infection by the Zika Virus (ZIKV) or pseudoparticles of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). At concentrations of >100 µg/mL, the three new Cm-p5 derivatives showed toxicity on different eukaryotic cells tested. Considering a certain cell toxicity but a potential interesting activity against the multiresistant strains of bacteria and HSV-2, our compounds require future structural optimization.

scholarly journals Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules

2005 ◽  
Vol 390 (2) ◽  
pp. 407-418 ◽  
Author(s):  
Catherine de Coupade ◽  
Antonio Fittipaldi ◽  
Vanessa Chagnas ◽  
Matthieu Michel ◽  
Sophie Carlier ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Mammalian Cells ◽  
Heparan Sulphate ◽  
Intracellular Delivery ◽  
Membrane Lipid ◽  
Cell Penetrating Peptides ◽  
Heparin Binding ◽  
Independent Manner ◽  
Cell Penetrating

Short peptide sequences that are able to transport molecules across the cell membrane have been developed as tools for intracellular delivery of therapeutic molecules. This work describes a novel family of cell-penetrating peptides named Vectocell® peptides [also termed DPVs (Diatos peptide vectors)]. These peptides, originating from human heparin binding proteins and/or anti-DNA antibodies, once conjugated to a therapeutic molecule, can deliver the molecule to either the cytoplasm or the nucleus of mammalian cells. Vectocell® peptides can drive intracellular delivery of molecules of varying molecular mass, including full-length active immunoglobulins, with efficiency often greater than that of the well-characterized cell-penetrating peptide Tat. The internalization of Vectocell® peptides has been demonstrated to occur in both adherent and suspension cell lines as well as in primary cells through an energy-dependent endocytosis process, involving cell-membrane lipid rafts. This endocytosis occurs after binding of the cell-penetrating peptides to extracellular heparan sulphate proteoglycans, except for one particular peptide (DPV1047) that partially originates from an anti-DNA antibody and is internalized in a caveolar independent manner. These new therapeutic tools are currently being developed for intracellular delivery of a number of active molecules and their potentiality for in vivo transduction investigated.

scholarly journals Enhanced delivery of protein fused to cell penetrating peptides to mammalian cells

BMB Reports ◽  
2019 ◽  
Vol 52 (5) ◽  
pp. 324-329 ◽  
Author(s):  
Jung-Il Moon ◽  
Min-Joon Han ◽  
Shin-Hye Yu ◽  
Eun-Hye Lee ◽  
Sang-Mi Kim ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating

scholarly journals Chemical Composition, Antioxidant and Antibacterial Activity of Bunium persicum, Eucalyptus globulus, and Rose Water on Multidrug-Resistant Listeria Species

2018 ◽  
Vol 23 ◽  
pp. 2515690X1775131 ◽  
Author(s):  
Farhad Sharafati Chaleshtori ◽  
Mohamad Saholi ◽  
Reza Sharafati Chaleshtori
Keyword(s):  
Antimicrobial Activity ◽  
Antibacterial Activity ◽  
Essential Oil ◽  
Essential Oils ◽  
Eucalyptus Globulus ◽  
Multidrug Resistant ◽  
Bacterial Strains ◽  
Antioxidant Power ◽  
Listeria Species ◽  
Bunium Persicum

This research was aimed at investigating the antioxidant and antibacterial activity of Bunium persicum, Eucalyptus globulus, and rose water on multidrug-resistant Listeria species. The antibiotic resistance of Listeria spp obtained from seafood samples were determined by the Kirby-Bauer method. The antioxidant and antibacterial activity of the essential oils and extracts were evaluated using ferric reducing antioxidant power and microdilution methods, respectively. A total 2 samples (1.88%) were positive for Listeria spp. L monocytogenes was found to be resistant to ampicillin, amoxicillin/clavulanic acid, penicillin, vancomycin, and kanamycin. B persicum essential oil showed the greatest antioxidant activity (248.56 ± 1.09 µM Fe2+/g). The E globulus essential oil showed consistently strong antimicrobial activity against L monocytogenes and L grayi, while rose water showed no antimicrobial activity against any of the tested bacterial strains. The results showed that after adding the B persicum and E globulus essential oils to bacteria, the cell components’ release increased significantly.

scholarly journals Neuropilin-1 and heparan sulfate proteoglycans cooperate in cellular uptake of nanoparticles functionalized by cationic cell-penetrating peptides

2015 ◽  
Vol 1 (10) ◽  
pp. e1500821 ◽  
Author(s):  
Hong-Bo Pang ◽  
Gary B. Braun ◽  
Erkki Ruoslahti
Keyword(s):  
Cell Surface ◽  
Heparan Sulfate ◽  
Vascular Permeability ◽  
Mammalian Cells ◽  
Cell Penetrating Peptides ◽  
Proteolytic Processing ◽  
Cell Surface Receptor ◽  
Neuropilin 1 ◽  
Cell Penetrating ◽  
Surface Receptor

Cell-penetrating peptides (CPPs) have been widely used to deliver nanomaterials and other types of macromolecules into mammalian cells for therapeutic and diagnostic use. Cationic CPPs that bind to heparan sulfate (HS) proteoglycans on the cell surface induce potent endocytosis; however, the role of other surface receptors in this process is unclear. We describe the convergence of an HS-dependent pathway with the C-end rule (CendR) mechanism that enables peptide ligation with neuropilin-1 (NRP1), a cell surface receptor known to be involved in angiogenesis and vascular permeability. NRP1 binds peptides carrying a positive residue at the carboxyl terminus, a feature that is compatible with cationic CPPs, either intact or after proteolytic processing. We used CPP and CendR peptides, as well as HS- and NRP1-binding motifs from semaphorins, to explore the commonalities and differences of the HS and NRP1 pathways. We show that the CendR-NRP1 interaction determines the ability of CPPs to induce vascular permeability. We also show at the ultrastructural level, using a novel cell entry synchronization method, that both the HS and NRP1 pathways can initiate a macropinocytosis-like process and visualize these CPP-cargo complexes going through various endosomal compartments. Our results provide new insights into how CPPs exploit multiple surface receptor pathways for intracellular delivery.

scholarly journals In Vitro Bactericidal Activity of Human β-Defensin 3 against Multidrug-Resistant Nosocomial Strains

2006 ◽  
Vol 50 (2) ◽  
pp. 806-809 ◽  
Author(s):  
Giuseppantonio Maisetta ◽  
Giovanna Batoni ◽  
Semih Esin ◽  
Walter Florio ◽  
Daria Bottai ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Activity ◽  
Bactericidal Activity ◽  
Stenotrophomonas Maltophilia ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Bacterial Strains ◽  
Gram Negative

ABSTRACT The antimicrobial activity of human β-defensin 3 (hBD-3) against multidrug-resistant clinical isolates of Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter baumannii was evaluated. A fast bactericidal effect (within 20 min) against all bacterial strains tested was observed. The presence of 20% human serum abolished the bactericidal activity of hBD-3 against gram-negative strains and reduced the activity of the peptide against gram-positive strains.

Stereochemistry as a determining factor for the effect of a cell-penetrating peptide on cellular viability and epithelial integrity

2018 ◽  
Vol 475 (10) ◽  
pp. 1773-1788 ◽  
Author(s):  
Ditlev Birch ◽  
Malene V. Christensen ◽  
Dan Staerk ◽  
Henrik Franzyk ◽  
Hanne Mørck Nielsen
Keyword(s):  
Amino Acids ◽  
Cell Viability ◽  
Mammalian Cells ◽  
Membrane Integrity ◽  
Cell Penetrating Peptides ◽  
Proliferating Cells ◽  
Epithelial Integrity ◽  
Cell Penetrating ◽  
Culture Models ◽  
Well Differentiated

Cell-penetrating peptides (CPPs) comprise efficient peptide-based delivery vectors. Owing to the inherent poor enzymatic stability of peptides, CPPs displaying partial or full replacement of l-amino acids with the corresponding d-amino acids might possess advantages as delivery vectors. Thus, the present study aims to elucidate the membrane- and metabolism-associated effects of l-Penetratin (l-PEN) and its corresponding all-d analog (d-PEN). These effects were investigated when exerted on hepatocellular (HepG2) or intestinal (Caco-2 and IEC-6) cell culture models. The head-to-head comparison of these enantiomeric CPPs included evaluation of their effects on cell viability and morphology, epithelial membrane integrity, and cellular ultrastructure. In all investigated cell models, a rapid decrease in cell viability, pronounced membrane perturbation and an altered ultrastructure were detected upon exposure to d-PEN. At equimolar concentrations, these observations were less pronounced or even absent for cells exposed to l-PEN. Both CPPs remained stable for at least 2 h during exposure to proliferating cells (cultured for 24 h), although d-PEN exhibited a longer half-life when compared with that of l-PEN when exposed to well-differentiated cell monolayers (cultured for 18–20 days). Thus, the stereochemistry of the CPP penetratin significantly influences its effects on cell viability and epithelial integrity when profiled against a panel of mammalian cells.

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