2011
DOI: 10.1038/ja.2011.43
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Design and syntheses of gramicidin S analogs, cyclo(-X-Leu-X-D-Phe-Pro-)2 (X=His, Lys, Orn, Dab and Dap)

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Cited by 8 publications
(4 citation statements)
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“…Its amphiphilic character with the aliphatic Val and Leu side chains oriented to one side and the cationic Orn side chains to the opposite direction forms the basis for the antimicrobial activity of GS toward a wide range of Gram-positive and Gram-negative bacteria by interacting with the lipid bilayer, lowering its integrity and ultimately causing cell death. Bacterial resistance develops more slowly against antibiotics targeting the cell membrane than against other modes of action, but the unwanted hemolytic activity restricts the use of GS beyond topical applications. , In spite of the many efforts and numerous GS analogues which were synthesized in the past 40 years, it was not possible to separate and suppress this unspecific membrane activity in a structure-based approach. Several investigations report ring contractions, ring expansions, mutations in the β-sheet and in the β-turn region, natural or non-natural amino acids, and their influence on the antimicrobial and hemolytic activity of GS . Here, we describe a novel approach to the problem of unspecific membrane affinity of GS: We systematically scale its membrane affinity by linking the peptide with different types of membrane anchors in a modular way. We introduce Dyp at the position of Pro as the smallest possible dihydroxylation of GS .…”
Section: Introductionmentioning
confidence: 84%
“…Its amphiphilic character with the aliphatic Val and Leu side chains oriented to one side and the cationic Orn side chains to the opposite direction forms the basis for the antimicrobial activity of GS toward a wide range of Gram-positive and Gram-negative bacteria by interacting with the lipid bilayer, lowering its integrity and ultimately causing cell death. Bacterial resistance develops more slowly against antibiotics targeting the cell membrane than against other modes of action, but the unwanted hemolytic activity restricts the use of GS beyond topical applications. , In spite of the many efforts and numerous GS analogues which were synthesized in the past 40 years, it was not possible to separate and suppress this unspecific membrane activity in a structure-based approach. Several investigations report ring contractions, ring expansions, mutations in the β-sheet and in the β-turn region, natural or non-natural amino acids, and their influence on the antimicrobial and hemolytic activity of GS . Here, we describe a novel approach to the problem of unspecific membrane affinity of GS: We systematically scale its membrane affinity by linking the peptide with different types of membrane anchors in a modular way. We introduce Dyp at the position of Pro as the smallest possible dihydroxylation of GS .…”
Section: Introductionmentioning
confidence: 84%
“…Compared with the widely investigated impacts of ring size and β-turn region, modifications of the β-strand region received little attention after the 1990s. Nevertheless, extending the molecular ring size or modifying the β-turn region bears the risk of disrupting the β-hairpin structure and suppressing the amphiphilicity. In contrast, replacement of amino acids of the β-strand region usually does not perturb the β-hairpin content, provided that the relative chirality ( d or l ) at each position is preserved.…”
Section: Structure–activity Relationship Of Gramicidin S and Its Anal...mentioning
confidence: 99%
“…When designing derivatives of our initial hit, we advantageously used the results of numerous SAR studies that are available in the literature on the parent molecule GS. ,,, These studies had been performed in vitro using assays similar to the ones we chose for our study. All previous studies had been aimed at improving the antibacterial activity of GS and decreasing its hemolytic toxicity.…”
Section: Resultsmentioning
confidence: 99%
“…This approach yielded analogues that retained the high antimicrobial activity of GS while offering 7- to 38-fold higher antibacterial selectivity (measured as the concentration causing 100% hemolysis divided by MIC, HC 100 /MIC). , This breakthrough was followed by a series of reports that achieved a moderate to high (up to 10-fold) improvement in the antibacterial therapeutic index (HC 100 /MIC or HC 50 /MIC) compared to that of GS by other structural changes. Namely, beneficial effects on the antibacterial selectivity were observed upon making alterations such as introducing positively charged moieties or aminoacylated residues at one , or both of the Pro sites, by replacing d -Phe at the β-turn with para-substituted d -Phe analogues or with pyridine-containing dehydroamino acids, by increasing the net charge in “inverted” GS analogues containing four positively charged and two β-branched bulky hydrophobic amino acid residues in the β-sheet fragment, by N -methylation of the backbone at the β-strand and β-turn regions, and by replacing the β-turn with hydroxy- and oxygen-containing mimics. , …”
Section: Resultsmentioning
confidence: 99%