title: Macrocyclic hairpin mimetics of the cationic antimicrobial peptide protegrin I: a new family of broad-spectrum antibiotics.
abstract: 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.
authors.affiliation: Institute of Organic Chemistry University of Zürich Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Sasalu C
authors.initials: SC
authors.lastname: Shankaramma
authors.forename: Zafiria
authors.initials: Z
authors.lastname: Athanassiou
authors.forename: Oliver
authors.initials: O
authors.lastname: Zerbe
authors.forename: Kerstin
authors.initials: K
authors.lastname: Moehle
authors.forename: Carole
authors.initials: C
authors.lastname: Mouton
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernardini
authors.forename: Jan W
authors.initials: JW
authors.lastname: Vrijbloed
authors.forename: Daniel
authors.initials: D
authors.lastname: Obrecht
authors.forename: John A
authors.initials: JA
authors.lastname: Robinson
mesh_terms: 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*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D010456:Peptides, Cyclic; D011506:Proteins; C094880:protegrin-1