Synthesis and Antimicrobial Evaluation of Amphiphilic Neamine Derivatives

Baussanne, Isabelle; Bussière, Antoine; Halder, Somnath; Ganem‐Elbaz, Carine; Ouberaï, Myriam; Riou, Mickaël; Paris, Jean‐Marc; Ennifar, Eric; Mingeot‐Leclercq, Marie‐Paule; Décout, Jean‐Luc

doi:10.1021/jm900615h

Cited by 64 publications

(87 citation statements)

References 31 publications

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“…Antibacterial activity of amphiphilic tobramycin R Dhondikubeer et al and others, 7,8 which have shown that conversion of the nonamphiphilic aminoglycosides neomycin-B and kanamycin-A into amphiphilic aminoglycosides enhances antibacterial activity against aminoglycoside-resistant and multidrug-resistant Gram-positive bacteria. [3][4][5] The compounds were selected to explore how the nature of the cationic aminoglycoside-based headgroup, the number of cationic charges and the nature of the hydrophobic lipid tail affects antibacterial activity in this class of compounds.…”

Section: Resultsmentioning

confidence: 99%

“…[3][4][5][6][7] For instance, when compared with their parent aminoglycosides, both neomycin-B-based hexacationic C 16 -lipid 7 or kanamycin-A-based tetracationic lipid C 16 -lipid 6 ( Figure 1) displayed 64-to 32-fold enhanced antibacterial activity against methicillin-resistant Staphylococcus aureus, whereas a 4-to 8-fold decrease in MIC was observed against two Pseudomonas aeruginosa strains. 4 Similarly, conjugation of neomycin-B and kanamycin-A to an ultrashort hydrophobic dipeptide led to a 16-fold lower MIC against methicillin-resistant Staphylococcus aureus and a 4-to 32-fold lower MIC against Pseudomonas aeruginosa strains.…”

Section: Introductionmentioning

confidence: 99%

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Antibacterial activity of amphiphilic tobramycin

et al. 2012

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Amphiphilic aminoglycoside antimicrobials are an emerging class of new antibacterial agents with novel modes of action. Previous studies have shown that amphiphilic neomycin-B and kanamycin-A analogs restore potent antibacterial activity against Gram-positive neomycin-B-and kanamycin-A-resistant organisms. In this paper, we investigated the antibacterial properties of a series of amphiphilic tobramycin analogs. We prepared tobramycin-lipid conjugates, as well as tobramycin-peptide triazole conjugates, and studied their antibacterial activities against a panel of Gram-positive and Gram-negative bacterial strains, including isolates obtained from Canadian hospitals. Our results demonstrate that the antibacterial activity of amphiphilic tobramycin is greatly affected by the length and nature of the hydrophobic lipid tail, whereas the nature of the polycationic headgroup or the number of cationic charges appear to be less important. Replacement of the hydrophobic tail by a fluorinated lipid confers good activity against two Pseudomonas strains and reduces hemolytic activity. However, susceptibility studies in the presence of bovine serum albumin indicate that all amphiphilic tobramycin analogs are strongly protein-bound, leading to a typical four-to eight-fold increase in MIC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antibacterial activity of amphiphilic tobramycin

et al. 2012

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“…The outer membrane of Pseudomonas is considered particularly impermeable due to the unusual tight packing of acyl chains. In the search for new antibiotics active on bacterial membranes, we synthesized a library of more than 60 amphiphilic neamine derivatives (27,29,30). Three 3=,6-dialkyl neamine derivatives (3=,6-diNn, 3=,6-di2NP, and 3=,6-di2NB) were shown to be active against Gram-positive and Gram-negative strains and to have low cytotoxicity (29).…”

Section: Discussionmentioning

confidence: 99%

“…The 3=, 6- [(2Љ-naphthyl)methyl]neamine (3=,4=,6-tri2NM) derivatives (Fig. 1) were synthesized in three steps from neamine according to our previous reports (27,29,30) by (i) tritylation of the four amine functions, (ii) alkylation with 1-bromononane or the corresponding bromonaphthylalkane in dimethyl formamide (DMF) in the presence of NaH or under phase transfer conditions with toluene and a concentrated aqueous solution of sodium hydroxide using tetrabutylammonium iodide or fluoride as the phase transfer agent, and (iii) removal of the trityl protective groups in the presence of trifluoroacetic acid-anisole. All compounds were isolated as tetratrifluoroacetates.…”

Section: Methodsmentioning

confidence: 99%

“…1) has shown antibacterial activity against both susceptible and resistant Gram-positive and Gramnegative bacteria, such as methicillin-resistant Staphylococcus au-reus, vancomycin-resistant Staphylococcus aureus, multiresistant P. aeruginosa, and Escherichia coli strains (27). In contrast to conventional aminoglycosides, this derivative was unable to bind to 16S rRNA in vitro and to inhibit P. aeruginosa protein synthesis (27) but, rather, was able to interact with LPS and induce P. aeruginosa membrane depolarization (28). Both effects suggest that this molecule possesses a novel mode of action related to its amphiphilic character, which allows it to bind to bacterial membranes, leading to their destabilization.…”

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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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Synthesis of Aminoglycosides

Berkov-Zrihen

Fridman

2013

Modern Synthetic Methods in Carbohydrate Chemistry

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Synthesis and Antimicrobial Evaluation of Amphiphilic Neamine Derivatives

Cited by 64 publications

References 31 publications

Antibacterial activity of amphiphilic tobramycin

Antibacterial activity of amphiphilic tobramycin

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

Synthesis of Aminoglycosides

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