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Cationic Antimicrobial Peptides (AMPs): Thermodynamic Characterization of Peptide-Lipid Interactions and Biological Efficacy of Surface-Tethered Peptides.

Bagheri M - ChemistryOpen (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Institute of Biochemistry & Biophysics, University of Tehran P.O. Box: 13145-1365, 16 Azar St., 1417614411, Tehran, Iran.

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Unlike the cholesterol-rich electrically neutral lipid membrane of eukaryotic cells, responsible for low peptide affinity and insertion, the bacterial cytoplasmic membrane possesses negatively charged phospholipids that, together with additional cellular envelope features such as the lipopolysaccharide (LPS) and peptidoglycans in Gram-negative and Gram-positive bacteria, respectively, represent ideal targets for cationic AMPs binding... In this doctoral research, the structural basis of activity of short cyclic AMPs rich in arginine and tryptophan residues, as promising anti-E.  coli candidates, was studied to understand membrane constituents and the peptide structural motif important for selectivity against Gram-negative bacteria... In particular, we sought to understand how a) the physical properties of the resin, such as the spacer length between the solid matrix and the AMP, as well as the capacity of the functional groups on the surface, and b) the tethering at different positions (peptide termini and side chain) affect the activities of the tethered AMPs. cyclo-RRRWFW (c-WFW) shows excellent activities against various strains of bacteria (in particular Gram-negative such as E.  coli) compared with its linear analogue, Ac-RRRWFW (Ac-WFW)... The roles of both the arginine and tryptophan residues in biological and bilayer permeabilizing activities are described for several peptide variants... The susceptibility of Gram-negative bacteria to c-WFW was proposed to be associated with factors that facilitate the transport of the peptide across the LPS. c-WFW is most active against the smooth LPS strain (wild type), while reduction of sugar chains in mutated LPS strain (rough type) distinctly decreases the antimicrobial effect... While the significant role of tryptophan residues in many LPS-binding motifs of AMPs is known, studies on the structural motifs of c-WFW in particular from the point of selective interactions between the aromatic side chain of tryptophan residues and distinct regions of LPS, which are important for its anti-E.  coli activity, needed to be done... In the presence of lipid A, rough-LPS and smooth-LPS, the dominant role of hydrophobicity decreased among the cyclic peptides with no influence on the weak affinity of the highly flexible linear Ac-WFW... The higher hydrophobic partition coefficients for the peptide interaction with POPC/smooth-LPS compared with POPC/rough-LPS lipid bilayers underlined the modulating effects of the O-antigen and the oligosaccharides in the outer core of LPS in the peptide activity and transport across the E.  coli outer wall... Specifically, the distance between the solid surface and the active sequences was identified as a critical parameter for peptide activity... The AMPs effectiveness decreased with decreasing spacer length, regardless of the amount of peptide on the surface... Immobilization of membrane-permeabilizing sequences was found to be most suitable for the generation of antimicrobial surfaces... Immobilization did not influence the activity pattern and conserved the peptide membrane-permeabilizing mode of action.

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Antimicrobial activities of free soluble and tethered AMPs. Number and letters in parentheses indicate the position of the peptide amino acid side chain or terminus at which immobilization occurred. Anti-B. subtilis activities of tethered BUF2 were not determined.
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fig03: Antimicrobial activities of free soluble and tethered AMPs. Number and letters in parentheses indicate the position of the peptide amino acid side chain or terminus at which immobilization occurred. Anti-B. subtilis activities of tethered BUF2 were not determined.

Mentions: The antimicrobial activities of free soluble and tethered peptides against E. coli and B. subtilis represent the major findings of this work. Specifically, the distance between the solid surface and the active sequences was identified as a critical parameter for peptide activity. The AMPs effectiveness decreased with decreasing spacer length, regardless of the amount of peptide on the surface. Immobilization of membrane-permeabilizing sequences was found to be most suitable for the generation of antimicrobial surfaces. Immobilization did not influence the activity pattern and conserved the peptide membrane-permeabilizing mode of action. Tethered AMPs showed anti-E. coli and anti-B. subtilis activities at millimolar concentrations compared with the micromolar concentrations of the free soluble peptides (Figure 3). The positioning of the peptides within the bacterial membrane, which is determined by the distribution of hydrophobic and charged residues in the sequence, has to be taken into account. In order to conserve high activity, tethering should occur at a position far away from the hydrophobic domain (c.f., activity of MEL tethered at the C and N terminus; Figure 3). In contrast, the activity of sequences with a uniform or symmetric distribution of hydrophobic and positively charged amino acids, for example, KLAL, MK5E, and TP, is less dependent on the tethering position. Membrane-translocating peptides such as BUF2 were inactivated by immobilization. A comparison of the activities of soluble AMPs and peptides tethered at variable positions might also be helpful in gaining insight into the membrane selectivity of peptides.


Cationic Antimicrobial Peptides (AMPs): Thermodynamic Characterization of Peptide-Lipid Interactions and Biological Efficacy of Surface-Tethered Peptides.

Bagheri M - ChemistryOpen (2015)

Antimicrobial activities of free soluble and tethered AMPs. Number and letters in parentheses indicate the position of the peptide amino acid side chain or terminus at which immobilization occurred. Anti-B. subtilis activities of tethered BUF2 were not determined.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4522190&req=5

fig03: Antimicrobial activities of free soluble and tethered AMPs. Number and letters in parentheses indicate the position of the peptide amino acid side chain or terminus at which immobilization occurred. Anti-B. subtilis activities of tethered BUF2 were not determined.
Mentions: The antimicrobial activities of free soluble and tethered peptides against E. coli and B. subtilis represent the major findings of this work. Specifically, the distance between the solid surface and the active sequences was identified as a critical parameter for peptide activity. The AMPs effectiveness decreased with decreasing spacer length, regardless of the amount of peptide on the surface. Immobilization of membrane-permeabilizing sequences was found to be most suitable for the generation of antimicrobial surfaces. Immobilization did not influence the activity pattern and conserved the peptide membrane-permeabilizing mode of action. Tethered AMPs showed anti-E. coli and anti-B. subtilis activities at millimolar concentrations compared with the micromolar concentrations of the free soluble peptides (Figure 3). The positioning of the peptides within the bacterial membrane, which is determined by the distribution of hydrophobic and charged residues in the sequence, has to be taken into account. In order to conserve high activity, tethering should occur at a position far away from the hydrophobic domain (c.f., activity of MEL tethered at the C and N terminus; Figure 3). In contrast, the activity of sequences with a uniform or symmetric distribution of hydrophobic and positively charged amino acids, for example, KLAL, MK5E, and TP, is less dependent on the tethering position. Membrane-translocating peptides such as BUF2 were inactivated by immobilization. A comparison of the activities of soluble AMPs and peptides tethered at variable positions might also be helpful in gaining insight into the membrane selectivity of peptides.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Institute of Biochemistry & Biophysics, University of Tehran P.O. Box: 13145-1365, 16 Azar St., 1417614411, Tehran, Iran.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Unlike the cholesterol-rich electrically neutral lipid membrane of eukaryotic cells, responsible for low peptide affinity and insertion, the bacterial cytoplasmic membrane possesses negatively charged phospholipids that, together with additional cellular envelope features such as the lipopolysaccharide (LPS) and peptidoglycans in Gram-negative and Gram-positive bacteria, respectively, represent ideal targets for cationic AMPs binding... In this doctoral research, the structural basis of activity of short cyclic AMPs rich in arginine and tryptophan residues, as promising anti-E.  coli candidates, was studied to understand membrane constituents and the peptide structural motif important for selectivity against Gram-negative bacteria... In particular, we sought to understand how a) the physical properties of the resin, such as the spacer length between the solid matrix and the AMP, as well as the capacity of the functional groups on the surface, and b) the tethering at different positions (peptide termini and side chain) affect the activities of the tethered AMPs. cyclo-RRRWFW (c-WFW) shows excellent activities against various strains of bacteria (in particular Gram-negative such as E.  coli) compared with its linear analogue, Ac-RRRWFW (Ac-WFW)... The roles of both the arginine and tryptophan residues in biological and bilayer permeabilizing activities are described for several peptide variants... The susceptibility of Gram-negative bacteria to c-WFW was proposed to be associated with factors that facilitate the transport of the peptide across the LPS. c-WFW is most active against the smooth LPS strain (wild type), while reduction of sugar chains in mutated LPS strain (rough type) distinctly decreases the antimicrobial effect... While the significant role of tryptophan residues in many LPS-binding motifs of AMPs is known, studies on the structural motifs of c-WFW in particular from the point of selective interactions between the aromatic side chain of tryptophan residues and distinct regions of LPS, which are important for its anti-E.  coli activity, needed to be done... In the presence of lipid A, rough-LPS and smooth-LPS, the dominant role of hydrophobicity decreased among the cyclic peptides with no influence on the weak affinity of the highly flexible linear Ac-WFW... The higher hydrophobic partition coefficients for the peptide interaction with POPC/smooth-LPS compared with POPC/rough-LPS lipid bilayers underlined the modulating effects of the O-antigen and the oligosaccharides in the outer core of LPS in the peptide activity and transport across the E.  coli outer wall... Specifically, the distance between the solid surface and the active sequences was identified as a critical parameter for peptide activity... The AMPs effectiveness decreased with decreasing spacer length, regardless of the amount of peptide on the surface... Immobilization of membrane-permeabilizing sequences was found to be most suitable for the generation of antimicrobial surfaces... Immobilization did not influence the activity pattern and conserved the peptide membrane-permeabilizing mode of action.

No MeSH data available.