Adsorption of cyclic peptide analogous to gramicidin S and gratisin onto octadecylsilica stationary phase and bacterial cells

Tamaki, Makoto; Takimoto, Michiaki; Nozaki, Sukekatsu; Muramatsu, Ichiro

doi:10.1016/0378-4347(87)80241-4

Cited by 15 publications

(4 citation statements)

References 8 publications

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“…This change in the mode of interaction seems to be related to the changed topology of the molecules (and their general amphipathic pattern), which can directly affect the biological activity of the analogues. Changes in the interaction of peptides with membrane, and the effect on biological activity, have also been observed for amphipathic helical peptides with double enantiomeric substitutions [22,31], as well as for gramicidin S and gratisin cyclic analogues [32].…”

Section: Discussionmentioning

confidence: 89%

Diastereoisomeric analogues of gramicidin S: structure, biological activity and interaction with lipid bilayers

Jelokhani-Niaraki

Kondejewski

Farmer

et al. 2000

Biochemical Journal

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Analogues of a structurally equivalent version of theantimicrobial decameric cyclic peptide gramicidin S, GS10 [cyclo-(Val-Lys-Leu-d-Tyr-Pro)(2)], were designed to study theeffect of distortion in the beta-sheet/beta-turn structure of thecyclic peptide on its biological activity. In one approach, thehydrophobic nature of GS10 was conserved, and single amino acids in itsbackbone were replaced systematically with their correspondingenantiomers to give five diastereoisomeric analogues. In a relatedapproach, a more basic and hydrophilic analogue of GS10 [cyclo-(Lys-Val-Lys-d-Tyr-Pro(5)-Lys-Leu-Lys-d-Tyr-Pro(10))], together with two of itsmonosubstituted diastereoisomeric analogues (featuring d-Lys(1) or d-Val(2) respectively), weresynthesized. CD spectra were measured in a variety of environments,i.e. aqueous, aqueous trifluoroethanol and those containing SDSmicelles or phospholipid vesicles. In comparison with GS10 spectra, CDspectra of both groups of analogues in these environments exhibitedstructural distortion. Moreover, compared with GS10, antimicrobial andhaemolytic activities of the analogues were drastically decreased, implying the existence of a threshold minimum amphipathicity foreffective biological activity. However, in both groups of analogues,there was a correlation between amphipathicity and antimicrobial andhaemolytic activities. In the second group of analogues, bothelectrostatic and hydrophobic factors were related to theirantimicrobial and haemolytic activities. In order to gain an insightinto the nature of the biological activity of the two classes of cyclicpeptides, the relationship of their structure to interaction with lipidmembranes, and the implied mechanisms, were analysed in some detail inthe present study.

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Section: Discussionmentioning

confidence: 89%

Diastereoisomeric analogues of gramicidin S: structure, biological activity and interaction with lipid bilayers

Jelokhani-Niaraki

Kondejewski

Farmer

et al. 2000

Biochemical Journal

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“…The ␤-sheet structure gives the molecule a preformed amphipathic nature with four hydrophobic residues (Val and Leu) making up one face of the molecule and two basic Orn residues making up the other face. This amphipathicity, along with high hydrophobicity, has long been thought to be important for the antimicrobial properties of GS-like peptides (5,(15)(16)(17)(18). A previous study with cyclic ␤-sheet antimicrobial peptides based on GS indicated that it is possible to dissociate antimicrobial and hemolytic activities through gross manipulation of ␤-sheet structure and amphipathicity (19).…”

mentioning

confidence: 99%

Dissociation of Antimicrobial and Hemolytic Activities in Cyclic Peptide Diastereomers by Systematic Alterations in Amphipathicity

Kondejewski¹,

Jelokhani-Niaraki²,

Farmer³

et al. 1999

Journal of Biological Chemistry

236

243

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We have investigated the role of amphipathicity in a homologous series of head-to-tail cyclic antimicrobial peptides in efforts to delineate features resulting in high antimicrobial activity coupled with low hemolytic activity (i.e. a high therapeutic index). The peptide GS14, cyclo(VKLKVd-YPLKVKLd-YP), designed on the basis of gramicidin S (GS), exists in a preformed highly amphipathic ␤-sheet conformation and was used as the base compound for this study. Fourteen diastereomers of GS14 were synthesized; each contained a different single enantiomeric substitution within the framework of GS14. The ␤-sheet structure of all GS14 diastereomers was disrupted as determined by CD and NMR spectroscopy under aqueous conditions; however, all diastereomers exhibited differential structure inducibility in hydrophobic environments. Because the diastereomers all have the same composition, sequence, and intrinsic hydrophobicity, the amphipathicity of the diastereomers could be ranked based upon retention time from reversed-phase high performance liquid chromatography. There was a clear correlation showing that high amphipathicity resulted in high hemolytic activity and low antimicrobial activity in the diastereomers. The latter may be the result of increased affinity of highly amphipathic peptides to outer membrane components of Gram-negative microorganisms. The diastereomers possessing the most favorable therapeutic indices possessed some of the lowest amphipathicities, although there was a threshold value below which antimicrobial activity decreased. The best diastereomer exhibited 130-fold less hemolytic activity compared with GS14, as well as greatly increased antimicrobial activities, resulting in improvement in therapeutic indices of between 1,000-and 10,000-fold for a number of microorganisms. The therapeutic indices of this peptide were between 16-and 32-fold greater than GS for Gram-negative microorganisms and represents a significant improvement in specificity over GS. Our findings show that a highly amphipathic nature is not desirable in the design of constrained cyclic antimicrobial peptides and that an optimum amphipathicity can be defined by systematic enantiomeric substitutions.

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“…From these studies, a number of structural requirements believed to be important for GS activity have been determined. These include (i) the requirement for an amphipathic structure containing basic residues on the hydrophilic face of the molecule (4, 7), (ii) a ␤-sheet structure, or the ability to achieve a ␤-sheet structure in the presence of lipid bilayers (7,12), and (iii) a high overall hydrophobicity (3,13,14).…”

mentioning

confidence: 99%

Modulation of Structure and Antibacterial and Hemolytic Activity by Ring Size in Cyclic Gramicidin S Analogs

Kondejewski

Farmer

Wishart

et al. 1996

Journal of Biological Chemistry

176

234

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We have evaluated the effect of ring size of gramicidin S analogs on secondary structure, lipid binding, lipid disruption, antibacterial and hemolytic activity. Cyclic analogs with ring sizes ranging from 4 to 14 residues were designed to maintain the amphipathic character as found in gramicidin S and synthesized by solid phase peptide synthesis. The secondary structure of these peptides showed a definite periodicity in ␤-sheet content, with rings containing 6, 10, and 14 residues exhibiting ␤-sheet structure, and rings containing 8 or 12 residues being largely disordered. Peptides containing 4 or 6 residues did not bind lipopolysaccharide, whereas longer peptides showed a trend of increasing binding affinity for lipopolysaccharide with increasing length. Destabilization of Escherichia coli outer membranes was only observed in peptides containing 10 or more residues. Peptides containing fewer than 10 residues were completely inactive and exhibited no hemolytic activity. The 10-residue peptide showed an activity profile similar to that of gramicidin S itself, with activity against Grampositive and Gram-negative microorganisms as well as yeast, but also showed high hemolytic activity. Differential activities were obtained by increasing the size of the ring to either 12 or 14 residues. The 14-residue peptide showed no antibiotic activity but exhibited increased hemolytic activity. The 12-residue peptide lost activity against Gram-positive bacteria, retained activity against Gram-negative microorganisms and yeast, but displayed decreased hemolytic activity. Biological activities in the 12-residue peptide were optimized by a series of substitutions in residues comprising both hydrophobic and basic sites resulting in a peptide that exhibited activities comparable with gramicidin S against Gramnegative microorganisms and yeast but with substantially lower hemolytic activity. Compared with gramicidin S, the best analog showed a 10-fold improvement in antibiotic specificity for Gram-negative microorganisms and a 7-fold improvement in specificity for yeast over human erythrocytes as determined by a therapeutic index. These results indicate that it is possible to modulate structure and activities of cyclic gramicidin S analogs by varying ring sizes and further show the potential for developing clinically useful antibiotics based on gramicidin S.

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Adsorption of cyclic peptide analogous to gramicidin S and gratisin onto octadecylsilica stationary phase and bacterial cells

Cited by 15 publications

References 8 publications

Diastereoisomeric analogues of gramicidin S: structure, biological activity and interaction with lipid bilayers

Diastereoisomeric analogues of gramicidin S: structure, biological activity and interaction with lipid bilayers

Dissociation of Antimicrobial and Hemolytic Activities in Cyclic Peptide Diastereomers by Systematic Alterations in Amphipathicity

Modulation of Structure and Antibacterial and Hemolytic Activity by Ring Size in Cyclic Gramicidin S Analogs

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