Antimicrobial Peptide Dendrimer Chimera

Siriwardena, Thissa N.; Lüscher, Alexandre; Köhler, Thilo; Delden, Christian van; Javor, Sacha; Reymond, Jean‐Louis

doi:10.1002/hlca.201900034

Cited by 29 publications

(44 citation statements)

References 48 publications

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“…However, due to the toxicity of polymyxins (13,14) and the emergence of resistance against colistin in clinical settings, alternative AMPs are warranted (15)(16)(17). We recently reported the synthesis of a group of dendrimer AMPs, characterized by a synthetic branched-chain peptide scaffold consisting exclusively of D-Leu and D-Arg amino acid residues (18)(19)(20). The dendrimer molecules tested here are characterized by MWs of 4,500 to 5,000 Da and present 15 to 17 positive charges at neutral pH.…”

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confidence: 99%

Adaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosa

Jeddou

Falconnet

Lüscher

et al. 2020

Antimicrob Agents Chemother

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Colistin (polymyxin E) is a last-resort antibiotic against multidrug-resistant isolates of Pseudomonas aeruginosa. However, the nephro-toxicity of colistin limits its use, spurring the interest in novel antimicrobial peptides (AMP). Here, we show that the synthetic AMP-dendrimer G3KL (MW 4,531.38 Da, 15 positive charges, MIC = 8 mg/liter) showed faster killing than polymyxin B (Pmx-B) with no detectable resistance selection in P. aeruginosa strain PA14. Spontaneous mutants selected on Pmx-B, harboring loss of function mutations in the PhoQ sensor kinase gene, showed increased Pmx-B MICs and arnB operon expression (4-amino-l-arabinose addition to lipid A), but remained susceptible to dendrimers. Two mutants carrying a missense mutation in the periplasmic loop of the PmrB sensor kinase showed increased MICs for Pmx-B (8-fold) and G3KL (4-fold) but not for the dendrimer T7 (MW 4,885.64 Da, 16 positive charges, MIC = 8 mg/liter). The pmrB mutants showed increased expression of the arnB operon as well as of the speD2-speE2-PA4775 operon, located upstream of pmrAB, and involved in polyamine biosynthesis. Exogenous supplementation with the polyamines spermine and norspermine increased G3KL and T7 MICs in a phoQ mutant background but not in the PA14 wild type. This suggests that both addition of 4-amino-l-arabinose and secretion of polyamines are required to reduce susceptibility to dendrimers, probably neutralizing the negative charges present on the lipid A and the 2-keto-3-deoxyoctulosonic acid (KDO) sugars of the lipopolysaccharide (LPS), respectively. We further show by transcriptome analysis that the dendrimers G3KL and T7 induce adaptive responses through the CprRS two-component system in PA14.

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confidence: 99%

Adaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosa

Jeddou

Falconnet

Lüscher

et al. 2020

Antimicrob Agents Chemother

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“…In view of crystallizing dendrimer complexes with the fucose specific lectin LecB, we synthesized fucosylated analogs of two series of dendrimers for which previous data suggested the presence of secondary structures in the peptide branches. In the first series, we focused on analogs of G3KL and TNS18 , which are antimicrobial peptide dendrimers (AMDPs) active against multidrug resistant Gram‐negative bacteria and for which CD and MD studies point to either α ‐helical ( G3KL ) or β ‐sheet ( TNS18 ) secondary structures within the dendrimer . In the second case, we prepared analogs of FD2 , a biofilm inhibitory glycopeptide dendrimer, as a follow‐up on previously obtained X‐ray crystal structures of lectin complexes with glycosylated analogs of its terminal tripeptide branch and with a related first generation glycodendrimer …”

Section: Resultsmentioning

confidence: 99%

“…Herein, we report the crystal structure of a second‐generation peptide dendrimer ( SBD8 , PDB 6S5S). This structure provides the first direct structural insight into a broad class of peptide dendrimers developed in our group over the past 15 years as enzyme models, drug and nucleic acid delivery agents, biofilm inhibitors and antimicrobial agents, but for which structural models to date were built indirectly by molecular dynamics (MD) studies supported by DOSY NMR for size estimation and circular dichroism (CD) for secondary structure content …”

Section: Introductionmentioning

confidence: 99%

X‐Ray Crystal Structure of a Second‐Generation Peptide Dendrimer in Complex with Pseudomonas aeruginosa Lectin LecB

Baeriswyl

Javor

Stocker

et al. 2019

Helvetica Chimica Acta

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This publication is dedicated to Prof. Philippe Renaud on the occasion of his 60 th Birthday Dendrimers are regularly branched molecular trees which are notoriously difficult to crystallize. Herein we report the crystal structure of a C-fucosylated second generation peptide dendrimer as complex with lectin LecB in which the only dendrimer-lectin contact is the LecB bound glycoside (PDB 6S5S). In contrast to a previously reported crystal structure of a first-generation peptide dendrimer as LecB complex in which the dendrimer formed trimers connected by intermolecular β-sheets (PDB 5D2A), the present structure features a globular monomeric state held together by intramolecular backbone hydrogen bonds and assembled into a non-covalent dimer stabilized by hydrophobic contacts between leucine side-chains and proline-phenylalanine CH-π stacking interactions. Molecular dynamics and circular dichroism studies suggest that this crystal structure resembles the structure of the peptide dendrimer in solution. Structures of a partially resolved dendrimer (PDB 6S5R) and of Cfucosylated disulfide bridged peptide dimers connecting different LecB tetramers are also reported (PDB 6S7G, PDB 6S5P). Scheme 1. Synthesis of peptide dendrimer SBD8. a) Standard Fmoc SPPS; b) i. Pd(PPh 3 ) 4 (0.25 equiv.), PhSiH 3 (25 equiv.), CH 2 Cl 2 , 2 × 45 min., ii. Standard Fmoc SPPS, iii. Peracetylated α-Lfucosyl-acetic acid/Oxyma/DIC in NMP/CH 2 Cl 2 , overnight; c) i. MeOH/H 2 O/NH 3 ·25 % aq. (8:1:1), 24 h, ii. CF 3 CO 2 H/ i Pr 3 SiH/H 2 O (95 : 2.5 : 2.5), 3.5 h.Figure 5. Backbone structure representation of peptide dendrimers SBD8 (X-ray structure), TNS18 and G3KL (MD models) with backbone H-bonds highlighted as dashed black lines.

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“…The above discussion revealed that antimicrobial peptides are promising for the development of peptide-based novel therapeutics and an alternative to conventional antibiotics. [55][56][57] Moreover, antimicrobial peptides have got much attention to overcome the drug resistance due to their unique mechanism of interaction with the target pathogens. However, various factors such as selectivity, cytotoxicity, side effects, drug resistance, etc.…”

Section: Therapeutic Perspectives Of Antimicrobial Peptidesmentioning

confidence: 99%

Cationic Amphiphilic Peptides: Synthetic Antimicrobial Agents Inspired by Nature

Kundu

2020

ChemMedChem

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Antimicrobial peptides are ubiquitous in multicellular organisms and have served as defense mechanisms for their successful evolution and throughout their life cycle. These peptides are short cationic amphiphilic polypeptides of fewer than 50 amino acids containing either a few disulfide-linked cysteine residues with a characteristic β-sheet-rich structure or linear α-helical conformations with hydrophilic side chains at one side of the helix and hydrophobic side chains on the other side. Antimicrobial peptides cause bacterial cell lysis either by direct cellsurface damage via electrostatic interactions between the cationic side chains of the peptide and the negatively charged cell surface, or by indirect modulation of the host defense systems. Electrostatic interactions lead to bacterial cell membrane disruption followed by leakage of cellular components and finally bacterial cell death. Because of their unusual mechanism of cell damage, antimicrobial peptides are effective against drug-resistant bacteria and may therefore prove more effective than classical antibiotics in certain cases. Currently, around 3000 natural antimicrobial peptides from six kingdoms (bacteria, archaea, protists, fungi, plants, and animals) have been isolated and sequenced. However, only a few of them are under clinical trials and/or in the commercial development stage for the treatment of bacterial infections caused by antibiotic-resistant bacteria. Moreover, high structural complexity, poor pharmacokinetic properties, and low antibacterial activity of natural antimicrobial peptides hinder their progress in drug development. To overcome these hurdles, researchers have become increasingly interested in modification and nature-inspired synthetic antimicrobial peptides. This review discusses some of the recent studies reported on antimicrobial peptides.

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Antimicrobial Peptide Dendrimer Chimera

Cited by 29 publications

References 48 publications

Adaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosa

Adaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosa

X‐Ray Crystal Structure of a Second‐Generation Peptide Dendrimer in Complex with Pseudomonas aeruginosa Lectin LecB

Cationic Amphiphilic Peptides: Synthetic Antimicrobial Agents Inspired by Nature

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