Search

Background: This paper describes the antimicrobial activities of 20 lysine-peptoid hybrids against a selection of clinically relevant bacteria and fungi., Methods: Minimal inhibitory concentrations were determined against methicillin-susceptible Staphylococcus aureus (ATCC 29213), methicillin-resistant S. aureus (ATCC 33591), vancomycin-intermediate S. aureus (ATCC 700699 MU50), vancomycin-resistant Enterococcus faecium (ATCC 700221), Pseudomonas aeruginosa (ATCC 27853), Salmonella typhimurium (clinical isolate), Klebsiella pneumoniae (clinical isolate), amphotericin-B-resistant C. albicans (ATCC 200955) and Cryptococcus neoformans (clinical isolate)., Results: The lysine-peptoid hybrids proved to be active against all strains tested, except K. pneumoniae. For each susceptible strain, we identified at least 4 lysine-peptoid hybrids showing excellent activity. The most active compounds displayed minimal inhibitory concentrations ranging from < or =1.6 to 6.25 microM., Conclusion: This study demonstrates that lysine-peptoid hybrids show activity against drug-resistant pathogens.

In this paper, we describe the synthesis and screening of a biased positional scanning library made up of peptoids (N-alkylglycines) and lysines. The library consisted of 100 mixtures divided into four sub-libraries; OXXXKKK, XOXXKKK, XXOXKKK, and XXXOKKK, O being a defined peptoid building block and X a mixture of 25 peptoid building blocks. A theoretical number of 390,625 compounds were synthesized. The compound mixtures were screened against the American Type Culture Collection (ATCC) Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 bacterial strains, and the cytotoxic activities were assessed using a human blood hemolytic assay. The results from each sub-library were examined to identify the most potent amine at each position. On the basis of this knowledge eight new lysine-peptoid hybrids were synthesized and tested in the biological assays. One compound in particular, [N-(cyclohexylmethyl)glycyl]-[N-(1-methylhexyl)glycyl]-[N-(4-methylbenzyl)glycyl]-[N-(2-(3-chlorophenyl)ethyl)glycyl]-lysyl-lysyl-lysine amide, showed high antibacterial activity and low toxicity toward red blood cells.

Here we report the design, synthesis and antibacterial activity of 20 lysine-peptoid hybrids. The hybrids are based on the peptoid lead structure [N-(1-naphthalenemethyl)glycyl]-[N-(4-methylbenzyl)glycyl]-[N-(1-naphthalenemethyl)glycyl]-N-(butyl)glycin amide (1) and contain between one and six lysine residues each. The compounds were tested for antibacterial activity against S. aureus ATCC 25923 and E. coli ATCC 25922. Furthermore, the hemolytic activity toward human erythrocytes was assessed. Several compounds with potent antibacterial activity and low hemolytic activity were identified., (Copyright 2005 European Peptide Society and John Wiley & Sons, Ltd.)

Anoplin is a decapeptide amide, GLLKRIKTLL-NH2 derived from the venom sac of the solitary spider wasp, Anoplius samariensis. It is active against Gram-positive and Gram-negative bacteria and is not hemolytic towards human erythrocytes. The present paper reports a structure-activity study of anoplin based on 37 analogues including an Ala-scan, C- and N-truncations, and single and multiple residue substitutions with various amino acids. The analogues were tested for antibacterial activity against both S. aureus ATCC 25923 and E. coli ATCC 25922, and several potent antibacterial analogues were identified. The cytotoxicity of the analogues against human erythrocytes was assessed in a hemolytic activity assay. The antibacterial activity and selectivity of the analogues against S. aureus and E. coli varied considerably, depending on the hydrophobicity and position of the various substituted amino acids. In certain cases the selectivity for Gram-positive and Gram-negative bacteria was either reversed or altogether eliminated. In addition, it was generally found that antibacterial activity coincided with hemolytic activity., (Copyright 2004 European Peptide Society and John Wiley & Sons, Ltd.)

Indolicidin is a 13-residue antimicrobial peptide amide, ILPWKWPWWPWRR-NH2, isolated from the cytoplasmic granules of bovine neutrophils. Indolicidin is active against a wide range of microorganisms and has also been shown to be haemolytic and cytotoxic towards erythrocytes and human T lymphocytes. The aim of the present paper is two-fold. First, we examine the importance of tryptophan in the antibacterial activity of indolicidin. We prepared five peptide analogues with the format ILPXKXPXXPXRR-NH2 in which Trp-residues 4,6,8,9,11 were replaced in all positions with X = a single non-natural building block; N-substituted glycine residue or nonproteinogenic amino acid. The analogues were tested for antibacterial activity against both Staphylococcus aureus American type culture collection (ATCC) 25923 and Escherichia coli ATCC 25922. We found that tryptophan is not essential in the antibacterial activity of indolicidin, and even more active analogues were obtained by replacing tryptophan with non-natural aromatic amino acids. Using this knowledge, we then investigated a new principle for improving the antibacterial activity of small peptides. Our approach involves changing the hydrophobicity of the peptide by modifying the N-terminus with a hydrophobic non-natural building block. We prepared 22 analogues of indolicidin and [Phe(4,6,8,9,11)] indolicidin, 11 of each, carrying a hydrophobic non-natural building block attached to the N-terminus. Several active antibacterial analogues were identified. Finally, the cytotoxicity of the analogues against sheep erythrocytes was assessed in a haemolytic activity assay. The results presented here suggest that modified analogues of antibacterial peptides, containing non-natural building blocks, are promising lead structures for developing future therapeutics.