Quantitative Structure-Hydrophobicity and Structure-Activity Relationships of Antibacterial Gramicidin S Analogs

Katayama, Tadashi; Nakao, Kazuya; Akamatsu, Miki; Ueno, Tamio; Fujita, Toshio

doi:10.1002/jps.2600830930

Cited by 12 publications

(6 citation statements)

References 24 publications

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“…The dashed line corresponds to the assumption frequently used for ion correction that ion pair extraction is completely negligible [Eqs. (17) and (18) 53 This behavior contradicts the usual assumption that only the uncharged form partitions in the octanol phase, and suggests that the ionized form-probably only as an ion-pair complex-also enters this phase. [9][10]25,[52][53] At pH values sufficiently far from the compounds' pK a the partition of the ionized form might even become the major contributor to the apparent partition coefficient.…”

Section: Apparent Partition Coefficient For Some Monoionic Speciescontrasting

confidence: 47%

“…In addition, each NH 3 ϩ group of two Orn residues can hydrogen-bond with the backbone carbonyl of the D-Phe residues. 17,59 Assuming that when computing the apparent partition coefficients the effects of the two positively charged Lys or Orn residues can be described additively with the ⌬N ϭ Ϫ3 correction established earlier, and that ⌬N ϭ ϩ6 for the mentioned six transannular hydrogen bonds, the calculated values are in very good agreement with the measured ones: n ϭ 12, r 2 ϭ 0.922, ϭ 0.458, F ϭ 117.8. As these compounds are much larger than those used in developing the model, this agreement can be considered a good confirmation of the previous assumptions.…”

Section: Gramicidin S Analogsmentioning

confidence: 60%

“…17 All structures contain two lysine or two ornithine residues, and only the apparent partition coefficient could be determined, as log P for the neutral form was too high for reliable measurements. These peptides have an antiparallel ␤-pleated sheet structure stabilized by two pairs of transannular hydrogen bonds.…”

Section: Gramicidin S Analogsmentioning

confidence: 99%

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Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size-based model

Buchwald

Bodor

1998

Proteins

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A remarkably simple, molecular size-based model developed to predict octanol-water partition coefficients for organic compounds is tested on a set of 188 neutral peptides with available experimental partition data. Despite using only two parameters, it gives a promising correlation (r2 = 0.914; sigma = 0.455, F = 1978.0), and predictions are in a realistic range even for larger peptides (cyclosporin, melanotan, sandostatin) where common, overparametrized fragment methods become quite unreliable. Ion-pair partitioning and the extraction constant formalism is briefly reviewed to describe the sigmoidal lipophilicity profile of ionizable, nonzwitterionic peptides. It seems possible to extend the present model to estimate apparent partition coefficients measured around neutral pH and physiological conditions for monoionic peptides; however, as no standard conditions are yet defined and only relatively small number of experimental data are available, the situation here is more complex.

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Section: Apparent Partition Coefficient For Some Monoionic Speciescontrasting

confidence: 47%

Section: Gramicidin S Analogsmentioning

confidence: 60%

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Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size-based model

Buchwald

Bodor

1998

Proteins

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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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Quantitative Structure-Hydrophobicity and Structure-Activity Relationships of Antibacterial Gramicidin S Analogs

Cited by 12 publications

References 24 publications

Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size-based model

Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size-based model

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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