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(Received for publication, February 8, 1996, and in revised form, July 18, 1996)
From the 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
Volume 271, Number 41,
Issue of October 11, 1996
pp. 25261-25268
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
Department of Biochemistry and the Protein
Engineering Network of Centres of Excellence, University of Alberta,
Edmonton, Alberta, T6G 2S2, the § Department of
Microbiology and the Canadian Bacterial Diseases Network, University of
British Columbia, Vancouver, British Columbia, V6T 1Z3, and the
¶ Faculty of Pharmacy, University of Alberta, Edmonton,
Alberta, T6G 2N8, Canada
-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 Gram-positive 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 Gram-negative 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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