Antimicrobial specificity and hemolytic activity of cyclized basic amphiphilic β-structural model peptides and their interactions with phospholipid bilayers

doi:10.1016/0005-2736(93)90314-P

Biochimica et Biophysica Acta (BBA) - Biomembranes

Volume 1147, Issue 1, 8 April 1993, Pages 42-49

https://doi.org/10.1016/0005-2736(93)90314-P Get rights and content

Abstract

We synthesized a series of cyclic antiparallel β-sheet model peptides with various ring sizes, which were designed on the basis of a cyclic β-structural antibiotic, gramicidin S (GS); cyclo(Val-Orn-Leu-d-Phe-Pro)₂, and investigated in terms of their antimicrobial activity and specificity against Gram-positive and Gram-negative bacteria and lytic activity for human erythrocytes. In our planning, in order to compare the peptides with GS, d-Phe-Pro sequence forming β-turn in GS molecule remained unaltered and repeating sequences of alternately hydrophobic (Leu)-hydrophilic (Orn) residue were introduced into the β-structural parts. CD study in acidic liposomes as well as leakage study of carboxyfluorescein encapsulated in phospholipid vesicles indicated that the peptides strongly interacted with lipid bilayers by taking an amphiphilic β-structure. Antimicrobial study showed that although GS is active only against Gram-positive bacteria, the antimicrobial spectra of the model peptides transformed gradually to be active against Gram-negative ones and finally only against Gram-negative bacteria whose repeating sequences increased. It should be noted that the designed cyclic model peptides show antibacterial activity but accompany no hemolysis. This indicates that an appropriate hydrophobicity together with a proper orientation of hydrophilic (cationic) and hydrophobic groups in cyclic β-structural molecules can hold antimicrobial activity against both types of bacteria without damaging eukaryotic cells.

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Gramicidin S identified as a potent inhibitor for cytochrome bd-type quinol oxidase
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Gramicidin S, a cationic cyclic decapeptide, exhibits the potent antibiotic activity through perturbation of lipid bilayers of the bacterial membrane. From the screening of natural antibiotics, we identified gramicidin S as a potent inhibitor for cytochrome bd-type quinol oxidase from Escherichia coli. We found that gramicidin S inhibited the oxidase with IC₅₀ of 3.5 μM by decreasing V_max and the affinity for substrates but showed the stimulatory effect at low concentrations. Our findings would provide a new insight into the development of gramicidin S analogs, which do not share the target and mechanism with conventional antibiotics.
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Citation Excerpt :
To be clinically meaningful, antimicrobial peptides must have an effective concentration that does not exhibit toxicity to human cells [23]. The hemolytic activity of antimicrobial peptides against human erythrocytes is often used as a measure for their cytotoxicity and to estimate their therapeutic index [24,25]. In this study, we have shown that rDCD-1L had no hemolytic activity at all when assayed in PBS.
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Regular paperAntimicrobial specificity and hemolytic activity of cyclized basic amphiphilic β-structural model peptides and their interactions with phospholipid bilayers

Abstract

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochemistry

Synthetic Aspects of Biologically Active Cyclic Peptides-Gramicidin S and Tyrocidines

Infect. Immun.

Bull. Chem. Soc. Jpn.

Bull. Chem. Soc. Jpn.

Fukuoka Univ. Sci. Rep.

J. Gen. Microbiol.

Biochemistry

Science

Regular paper
Antimicrobial specificity and hemolytic activity of cyclized basic amphiphilic β-structural model peptides and their interactions with phospholipid bilayers