Macrocyclic hairpin mimetics of the cationic antimicrobial peptide protegrin I: a new family of broad-spectrum antibiotics.
The problems associated with increasing antibiotic resistance have stimulated great interest in newly discovered families of naturally occurring cationic antimicrobial peptides. These include protegrin, tachyplesin, and RTD-1, which adopt beta-hairpin-like structures. We report here an approach to novel peptidomimetics based on these natural products. The mimetics were designed by transplanting the cationic and hydrophobic residues onto a beta-hairpin-inducing template, either a D-Pro-L-Pro dipeptide or a xanthene derivative. The mimetics have good antimicrobial activity against Gram-positive and Gram-negative bacteria (minimal inhibitory concentration approximately 6-25 microgram mL(-1)). Analogues with improved selectivity for microbial rather than red blood cells (1 % hemolysis at 100 microgram mL(-1)) were identified from a small library prepared by parallel synthesis. Thus, it is possible to separate the antimicrobial and hemolytic activities in this class of mimetics. NMR studies on one mimetic revealed a largely unordered structure in water, but a transition to a regular beta-hairpin backbone conformation in the presence of dodecylphosphocholine micelles. This family of mimetics may provide a starting point for the optimization of antimicrobial agents of potential clinical value in the fight against multiple-drug-resistant microorganisms.
Shankaramma
Sasalu C
SC
Institute of Organic Chemistry University of Zürich Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Athanassiou
Zafiria
Z
Zerbe
Oliver
O
Moehle
Kerstin
K
Mouton
Carole
C
Bernardini
Francesca
F
Vrijbloed
Jan W
JW
Obrecht
Daniel
D
Robinson
John A
JA
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D010456:Peptides, Cyclic; D011506:Proteins; C094880:protegrin-1