End group modification: Efficient tool for improving activity of antimicrobial peptide analogues towards Gram-positive bacteria

Jahnsen, Rasmus O.; Sandberg-Schaal, Anne; Frimodt‐Møller, Niels; Nielsen, Hanne Mørck; Franzyk, Henrik

doi:10.1016/j.ejpb.2015.01.013

Cited by 22 publications

(36 citation statements)

References 36 publications

(18 reference statements)

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“…Therefore, it was considered most promising to continue exploration of structure‐activity relationships for fully fluorinated peptidomimetics. Also, in a previous study, end‐group modification had proved to be a useful tool for improvement of antimicrobial activity of similar peptidomimetics against the Gram‐positive S. aureus . Consequently, to simultaneously perform an evaluation of the effect of increased length of hydrophobic side chains, two distinct types of end group‐modified fluorinated analogs (see Figure ) were designed.…”

Section: Resultsmentioning

confidence: 99%

“…Consequently, to simultaneously perform an evaluation of the effect of increased length of hydrophobic side chains, two distinct types of end group‐modified fluorinated analogs (see Figure ) were designed. Both classes displayed N‐terminal attachment of substituted acetic acid moieties comprising pentafluorophenylacetyl (F 5 PhAc) and cyclohexylacetyl (cHexAc), which previously were identified as activity‐enhancing groups against Gram‐positive bacteria, as well as three other related groups: 3,4,5‐trifluorophenylacetyl (F 3 PhAc), 4‐chlorophenylacetyl ([4‐Cl‐Ph]Ac), and 5‐bromoindol‐3‐ylacetyl ([5‐Br‐indol]Ac). These end‐group modifications were considered suitable for exploring the influence exerted by different halogenated aromatic moieties and the cyclohexyl group on the activity profiles.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, α‐peptide/β‐peptoid hybrids, bearing fluorine atoms on the phenyl rings of the βNPhe residues, were recently found to possess high antibacterial potency against MRSP while exhibiting low hemolytic activity . Additionally, it has been shown that N‐terminal modifications constitute a useful tool for improving antimicrobial activity of α‐peptide/α‐peptoid peptidomimetics toward Gram‐positive bacteria …”

Section: Introductionmentioning

confidence: 99%

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Fluorinated antimicrobial lysine‐based peptidomimetics with activity against methicillin‐resistant Staphylococcus pseudintermedius

Molchanova

Hansen

Damborg

et al. 2018

Journal of Peptide Science

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Staphylococcus pseudintermedius is the predominant opportunistic pathogen in dogs causing primarily integumentary infections such as pyoderma and otitis. The worldwide emergence of methicillin-resistant S. pseudintermedius (MRSP) constitutes a significant health problem for companion animals in veterinary medicine. Thus, discovery of novel agents for treatment of MRSP-associated infections is highly warranted. In the present work, structure-activity relationships (based on testing of 37 peptidomimetics) have been explored with the aim of determining the influence of oligomer length as well as effect of fluorination, end-group modification, and length of hydrophobic side chains. Incorporation of fluorine atoms and elongation of hydrophobic side chains both conferred overall increased potency without significantly enhancing the hemolytic properties of the compounds. Importantly, it was found that when targeting MRSP, the peptidomimetic length could be reduced from 12 to 8 residues without substantial loss of antibacterial activity. By contrast, introduction of end-group modifications did not improve the activity against MRSP (10 strains tested), but conferred increased activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, albeit the concomitantly increased hemolytic properties resulted in a slightly lowered cell selectivity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fluorinated antimicrobial lysine‐based peptidomimetics with activity against methicillin‐resistant Staphylococcus pseudintermedius

Molchanova

Hansen

Damborg

et al. 2018

Journal of Peptide Science

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“…Sequence template approach is among of the most successful ways to design ultra short antimicrobial peptidomimetics based on balance between cationic (+2 to +9 charge) and hydrophobic residues (approximately 50%) [35,36]. Trp residues impart hydrophobicity along with a distinct ability to reside at membrane inter-phase improving antibacterial activity [20].…”

Section: Design and Synthesis Of Sequencesmentioning

confidence: 99%

“…N-terminal capping with lipids and small organic moieties having inherent biological properties is well known for antibacterial peptidomimetics, a number of Arg and Trp rich sequences have also been reported [22,23,36], however our designed molecules are unique as along with a pharmacophore role the aromatic N-terminal tags serve to enhance hydrophobicity of Trp, Arg rich template which in turn promoted self assembly in designed sequences.…”

Section: Mechanism Of Interactionmentioning

confidence: 99%

N-terminal aromatic tag induced self assembly of tryptophan–arginine rich ultra short sequences and their potent antibacterial activity

et al. 2015

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Multiple drug resistant (MDR) Staphylococcus aureus is among the most dreaded pathogens for human health in community as well as nosocomial environments. Here we report self assembling ultra short N-terminal modified peptidomimetics based on a template X-W3R4 (where, X = aromatic organic moiety) that show potent activity against multiple MDR S. aureus strains. The active sequences self assemble in water to form nano vesicle (140-190 nm diameter) with positive surface zeta potential and hydrophobic core of Trp residues/N-terminal tags. Further, lethal membrane depolarisation of MRSA cells and a concentration dependent leakage of calcein dye from artificial bacterial mimic membranes established membrane disruptive mode of action for designed sequences. We demonstarte role of N-terminal tag on nature of self assembly and envisage the origin of antibacterial activity to be conformationally aligned nanovesicles which upon interaction lead to disruption of bacterial cells. The designed cell selective nanovesicles may further be exploited towards in vivo applications as antibacterial agent alone or as vehicles for systemic anti-infective therapy. Fig. 3: CD spectra of designed sequences in different environments; water ( ), phosphate buffer ( ) and 50% TFE (v/v) ( ). In (a) Sequence 4, (b) sequence 5, (c) sequence 6 and (d) sequence 7. The spectrum was acquired at a sample concentration of 20 µg/mL. Fig. 4: Trptophan fluorescence spectra of designed sequences in different environments; water ( ), 10 mM Tris buffer ( ) DOPC ( ) DOPC/DOPG ( ) and DMSO ( ). In (a) Sequence 4, (b) sequence 5, (c) sequence 6 and (d) sequence 7. The spectrum was acquired at a sample concentration of 5 µg/mL.

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Lysine‐Based α‐Peptide/β‐Peptoid Peptidomimetics: Influence of Hydrophobicity, Fluorination, and Distribution of Cationic Charge on Antimicrobial Activity and Cytotoxicity

et al. 2017

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Multidrug-resistant bacteria pose a serious threat to public health worldwide. Previously, α-peptide/β-peptoid hybrid oligomers were found to display activity against Gram-negative multidrug-resistant bacteria. In the present work, the influence of hydrophobicity, fluorination, and distribution of cationic/hydrophobic residues on antimicrobial, hemolytic, and cytotoxic properties of α-peptide/β-peptoid hybrids were investigated. An array of 22 peptidomimetics was tested. Analogues with enhanced hydrophobicity were found to exhibit increased activity against Gram-positive bacteria. Incorporation of fluorinated residues into the peptidomimetics conferred increased potency against Gram-positive bacteria, while hemolytic properties and activity against Gram-negative bacteria depended on the degree and type of fluorination. Generally, shorter oligomers were less potent than the corresponding longer analogues. However, some short analogues exhibited equal or higher antimicrobial activity. The alternating hydrophobic/cationic design proved superior to other distribution patterns of cationic side chains and hydrophobic moieties.

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End group modification: Efficient tool for improving activity of antimicrobial peptide analogues towards Gram-positive bacteria

Cited by 22 publications

References 36 publications

Fluorinated antimicrobial lysine‐based peptidomimetics with activity against methicillin‐resistant Staphylococcus pseudintermedius

Fluorinated antimicrobial lysine‐based peptidomimetics with activity against methicillin‐resistant Staphylococcus pseudintermedius

N-terminal aromatic tag induced self assembly of tryptophan–arginine rich ultra short sequences and their potent antibacterial activity

Lysine‐Based α‐Peptide/β‐Peptoid Peptidomimetics: Influence of Hydrophobicity, Fluorination, and Distribution of Cationic Charge on Antimicrobial Activity and Cytotoxicity

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