Electrostatics and flexibility drive membrane recognition and early penetration by the antimicrobial peptide dendrimer bH1

Ravi, Harish Kumar; Stach, Michaela; Soares, Thereza A.; Darbre, Tamis; Reymond, Jean‐Louis; Cascella, M.

doi:10.1039/c3cc44912b

Cited by 32 publications

(42 citation statements)

References 19 publications

(12 reference statements)

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“…In contrast, amphiphilic neamine derivatives, which are more flexible than colistin, induced a large increase in membrane fluidity, leading to a facilitated insertion in the lipid bilayer. This extends the results published by others (58,59) who suggested a critical role for the flexibility of the molecule and disordering, especially against colistin-resistant strains. These are characterized by changes in lipid A structures leading to modifications of hydrophobicity and molecular packing of LPS (60)(61)(62)(63).…”

Section: Discussionsupporting

confidence: 90%

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas aeruginosa and Their Interactions with Lipopolysaccharides

Sautrey

Zimmermann

Deleu

et al. 2014

Antimicrob Agents Chemother

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The development of novel antimicrobial agents is urgently required to curb the widespread emergence of multidrug-resistant bacteria like colistin-resistant Pseudomonas aeruginosa. We previously synthesized a series of amphiphilic neamine derivatives active against bacterial membranes, among which 3=,6-di-O-[(2؆-naphthyl)propyl]neamine (3=,6-di2NP), 3=,6-di-O-[(2؆-naphthyl)butyl]neamine (3=,6-di2NB), and 3=,6-di-O-nonylneamine (3=,6-diNn) showed high levels of activity and low levels of cytotoxicity (L. Zimmermann et al., J. Med. Chem. 56:7691-7705, 2013). We have now further characterized the activity of these derivatives against colistin-resistant P. aeruginosa and studied their mode of action; specifically, we characterized their ability to interact with lipopolysaccharide (LPS) and to alter the bacterial outer membrane (OM). The three amphiphilic neamine derivatives were active against clinical colistin-resistant strains (MICs, about 2 to 8 g/ml), The most active one (3=,6-diNn) was bactericidal at its MIC and inhibited biofilm formation at 2-fold its MIC. They cooperatively bound to LPSs, increasing the outer membrane permeability. Grafting long and linear alkyl chains (nonyl) optimized binding to LPS and outer membrane permeabilization. The effects of amphiphilic neamine derivatives on LPS micelles suggest changes in the cross-bridging of lipopolysaccharides and disordering in the hydrophobic core of the micelles. The molecular shape of the 3=,6-dialkyl neamine derivatives induced by the nature of the grafted hydrophobic moieties (naphthylalkyl instead of alkyl) and the flexibility of the hydrophobic moiety are critical for their fluidifying effect and their ability to displace cations bridging LPS. Results from this work could be exploited for the development of new amphiphilic neamine derivatives active against colistin-resistant P. aeruginosa.

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Section: Discussionsupporting

confidence: 90%

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas aeruginosa and Their Interactions with Lipopolysaccharides

Sautrey

Zimmermann

Deleu

et al. 2014

Antimicrob Agents Chemother

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“…Several authors have modified AMPs to obtain proteolytically resistant versions, mostly by sequence variations and the use of D-amino acids (12-15). However, redesigning the peptide chain topology, in particular by introducing multiple branching points to obtain synthetic AMP dendrimers (AMPDs), seems a promising solution to overcome all of the the aforementioned problems (16-18).G3KL is a novel AMP dendrimer (AMPD) developed at the Department of Chemistry and Biochemistry of the University of Bern (Switzerland) by sequence optimization of an initial hit compound identified by screening a combinatorial library of dendrimers using a tailored high-throughput screening assay and presumed to act as a membrane-disrupting agent (19)(20)(21)(22). Its activity requires a dendritic topology and only natural lysine and leucine residues alternating in the branches (Fig.…”

mentioning

confidence: 99%

“…G3KL is a novel AMP dendrimer (AMPD) developed at the Department of Chemistry and Biochemistry of the University of Bern (Switzerland) by sequence optimization of an initial hit compound identified by screening a combinatorial library of dendrimers using a tailored high-throughput screening assay and presumed to act as a membrane-disrupting agent (19)(20)(21)(22). Its activity requires a dendritic topology and only natural lysine and leucine residues alternating in the branches (Fig.…”

mentioning

confidence: 99%

In Vitro Activity of the Novel Antimicrobial Peptide Dendrimer G3KL against Multidrug-Resistant Acinetobacter baumannii and Pseudomonas aeruginosa

Pires

Siriwardena

Stach

et al. 2015

Antimicrob Agents Chemother

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eThe in vitro activity of the novel antimicrobial peptide dendrimer G3KL was evaluated against 32 Acinetobacter baumannii (including 10 OXA-23, 7 OXA-24, and 11 OXA-58 carbapenemase producers) and 35 Pseudomonas aeruginosa (including 18 VIM and 3 IMP carbapenemase producers) strains and compared to the activities of standard antibiotics. Overall, both species collections showed MIC 50/90 values of 8/8 g/ml and minimum bactericidal concentrations at which 50% or 90% of strains tested are killed (MBC 50/90 ) of 8/8 g/ml. G3KL is a promising molecule with antibacterial activity against multidrug-resistant and extensively drug-resistant A. baumannii and P. aeruginosa isolates. The spread of Acinetobacter baumannii and Pseudomonas aeruginosa isolates that are resistant to carbapenem antibiotics due to the production of carbapenemases represents a serious threat (1). These strains are usually multidrug-resistant (MDR) due to the coexpression of mechanisms involving other classes of antibiotics, thus drastically limiting our therapeutic armamentarium (2-4). In particular, extensively drug-resistant (XDR) isolates are commonly detected worldwide (5), whereas the prevalence of pandrug-resistant (PDR) isolates is increasing worryingly in several countries (6-8). Therefore, novel antimicrobial strategies need to be rapidly developed.Recently, there has been a rising interest in evaluating naturally occurring or synthetic antimicrobial peptides (AMPs) with activity against prokaryotic membranes. This attention is due to their wide spectrum of activity against both Gram-positive and Gramnegative species, potent bactericidal activity, and ability to bypass common mechanisms of resistance that affect standard antibiotics (9, 10). However, several reasons have so far limited the clinical implementation of AMPs: (i) high susceptibility to degradation by endogenous and microbial proteases; (ii) toxicity due to the high concentration necessary to inhibit bacteria; and (iii) short half-life because of high protein binding (11). Several authors have modified AMPs to obtain proteolytically resistant versions, mostly by sequence variations and the use of D-amino acids (12-15). However, redesigning the peptide chain topology, in particular by introducing multiple branching points to obtain synthetic AMP dendrimers (AMPDs), seems a promising solution to overcome all of the the aforementioned problems (16-18).G3KL is a novel AMP dendrimer (AMPD) developed at the Department of Chemistry and Biochemistry of the University of Bern (Switzerland) by sequence optimization of an initial hit compound identified by screening a combinatorial library of dendrimers using a tailored high-throughput screening assay and presumed to act as a membrane-disrupting agent (19)(20)(21)(22). Its activity requires a dendritic topology and only natural lysine and leucine residues alternating in the branches (Fig. 1). This novel AMPD has demonstrated in vitro activity against several Gram-negative strains, low toxicity to human red blood cells (minimal hemolytic ...

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“…G3KL is another AMP dendrimer developed by sequence optimization of an initial hit compound identified by screening a combinatorial library of dendrimers using a tailored high‐throughput screening assay . It is presumed to act as a membrane‐disrupting agent.…”

Section: Branched Peptide Applicationsmentioning

confidence: 99%

Branched peptides as bioactive molecules for drug design

et al. 2018

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Peptides are regarded as good candidates for new biotherapeutics in medicine. Several peptides have already completed clinical development, with more than 60 peptide‐based drugs already on the market, and a further 500 derivatives currently in developmental stages. Branched peptides are an emerging class of synthetic molecules being assessed for drug development. Here, we review possible clinical uses of branched peptides, considering major features such as stability, half‐life, toxicity, and efficacy compared to monomeric peptides, biodistribution, as well as modifications, encapsulation, and conjugation to improve delivery or bypass drug resistance. We focus in particular on the use of branched peptides in oncology and infectious diseases.

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Electrostatics and flexibility drive membrane recognition and early penetration by the antimicrobial peptide dendrimer bH1

Cited by 32 publications

References 19 publications

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas aeruginosa and Their Interactions with Lipopolysaccharides

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas aeruginosa and Their Interactions with Lipopolysaccharides

In Vitro Activity of the Novel Antimicrobial Peptide Dendrimer G3KL against Multidrug-Resistant Acinetobacter baumannii and Pseudomonas aeruginosa

Branched peptides as bioactive molecules for drug design

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