The effect of lipidation and glycosylation on short cationic antimicrobial peptides

Grimsey, Elizabeth M; Collis, Dominic W. P.; Mikut, Ralf; Hilpert, Kai

doi:10.1016/j.bbamem.2020.183195

Cited by 75 publications

(73 citation statements)

References 62 publications

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“…These findings are in accordance with the results of this study and several studies published previously [18][19][20]. Longer fatty acids were found to form aggregates leading to a reduced antibacterial activity [16]. Time-kill studies revealed a bactericidal mode of action of Pep19-4LF and C11-Pep19-short.…”

Section: Discussionsupporting

confidence: 93%

“…This led to a significantly-higher peptide yield of 32%. In general, the results demonstrate that modification of antibacterial peptides with fatty acids can be a tool for improving the characteristics of antimicrobial peptides [15,16]. According to Galbraith et al, saturated fatty acids with 10 or 12 carbon atoms in chain length in general show the highest antimicrobial efficacy [17].…”

Section: Discussionmentioning

confidence: 82%

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Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

et al. 2020

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The increasing number of infections caused by multidrug-resistant bacteria requires an intensified search for new antibiotics. Pep19-4LF is a synthetic antimicrobial peptide (GKKYRRFRWKFKGKLFLFG) that was previously designed with the main focus on high antimicrobial activity. The hydrophobic motif, LFLFG, was found to be essential for antimicrobial activity. However, this motif shows several limitations such as aggregation in biological media, low solubility, and small yields in peptide synthesis. In order to obtain more appropriate peptide characteristics, the hydrophobic motif was replaced with fatty acids. For this purpose, a shortened variant of Pep19-4LF (Pep19-short; GKKYRRFRWKFKGK) was synthesized and covalently linked to saturated fatty acids of different chain lengths. The peptide conjugates were tested with respect to their antibacterial activity by microdilution experiments on different bacterial strains. The length of the fatty acid was found to be directly correlated to the antimicrobial activity up to an ideal chain length (undecanoic acid, C11:0). This conjugate showed high antimicrobial activity in absence of toxicity. Time–kill studies revealed a fast and bactericidal mode of action. Furthermore, the first in vivo experiments of the conjugate in rodents demonstrated pharmacokinetics appropriate for application as a drug. These results clearly indicate that the hydrophobic motif of the peptide can be replaced by a single fatty acid of medium length, simplifying the design of this antimicrobial peptide while retaining high antimicrobial activity in the absence of toxicity.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 82%

Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

et al. 2020

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“…It is well known that the strength of the interaction and the depth of internalisation into the target membrane are related to the antimicrobial capacity and that a strategy to improve interactions and activities is to increase the hydrophobicity 18 . In this context, a successful approach for increasing the hydrophobicity of charged peptides consists of the addition of saturated fatty acids with different carbon chain length at their N- or C-termini, since long lipid tails facilitate the incorporation into lipid bilayers 24–26 , induce a self-organisation into micelles in the bacterial membrane and improve the membrane permeabilisation 27 , 28 . Altogether these effects determine a fluidisation of bilayer and deformation of packing of the phospholipid acyl chain, inducing typically large channel formation and cell death 29 .…”

Section: Introductionmentioning

confidence: 99%

Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs

Bellavita

Falanga

Buommino

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The rapid development of antimicrobial resistance is pushing the search in the discovering of novel antimicrobial molecules to prevent and treat bacterial infections. Self-assembling antimicrobial peptides, as the lipidated peptides, are a novel and promising class of molecules capable of meeting this need. Based on previous work on Temporin L analogs, several new molecules lipidated at the Nor and the C-terminus were synthesised. Our goal is to improve membrane interactions through finely tuning self-assembly to reduce oligomerisation in aqueous solution and enhance self-assembly in bacterial membranes while reducing toxicity against human cells. The results here reported show that the length of the aliphatic moiety is a key factor to control target cell specificity and the oligomeric state of peptides either in aqueous solution or in a membrane-mimicking environment. The results of this study pave the way for the design of novel molecules with enhanced activities.

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“…Substitutions of L-amino acid with D-amino acid and the introduction of peptoid or proline (Pro) in the middle of an α-helical structure can induce bent structures, resulting in reduction of cytotoxicity of AMPs [ 56 , 57 , 58 , 59 ]. Enantiomerization, PEGylation, lipidation, and cyclization can enhance the bioavailability of AMPs and their specificity toward gram-negative bacterial membranes [ 60 , 61 ]. These variable methods are effective ways to increase the selectivity of AMP against the gram-negative bacterial membrane, resulting in increased therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

“…There are many potent natural AMPs with long amino acid sequences, but their use may be limited due to their length. For example, papiliocin with 37 amino acids shows high antibacterial activity against gram-negative bacteria; however, 37 residues can make the production costs high [ 61 ]. Previously, we designed 12-meric AMP analogs from the N-terminus of papiliocin with antiseptic activity against gram-negative infections [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models

Krishnan

Choi

Jang

et al. 2020

IJMS

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Owing to the challenges faced by conventional therapeutics, novel peptide antibiotics against multidrug-resistant (MDR) gram-negative bacteria need to be urgently developed. We had previously designed Pro9-3 and Pro9-3D from the defensin of beetle Protaetia brevitarsis; they showed high antimicrobial activity with cytotoxicity. Here, we aimed to develop peptide antibiotics with bacterial cell selectivity and potent antibacterial activity against gram-negative bacteria. We designed 10-meric peptides with increased cationicity by adding Arg to the N-terminus of Pro9-3 (Pro10-1) and its D-enantiomeric alteration (Pro10-1D). Among all tested peptides, the newly designed Pro10-1D showed the strongest antibacterial activity against Escherichia coli, Acinetobacter baumannii, and MDR strains with resistance against protease digestion. Pro10-1D can act as a novel potent peptide antibiotic owing to its outstanding inhibitory activities against bacterial film formation with high bacterial cell selectivity. Dye leakage and scanning electron microscopy revealed that Pro10-1D targets the bacterial membrane. Pro10-1D inhibited inflammation via Toll Like Receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) signaling pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Furthermore, Pro10-1D ameliorated multiple-organ damage and attenuated systemic infection-associated inflammation in an E. coli K1-induced sepsis mouse model. Overall, our results suggest that Pro10-1D can potentially serve as a novel peptide antibiotic for the treatment of gram-negative sepsis.

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The effect of lipidation and glycosylation on short cationic antimicrobial peptides

Cited by 75 publications

References 62 publications

Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models

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