ABSTRACT
The properties and structure-activity relationships (SAR) of a macrocyclic analogue of porcine protegrin I (PG-I) have been investigated. The lead compound, having the sequence cyclo-(-Leu-Arg-Leu-Lys-Lys-Arg-Arg-Trp-Lys-Tyr-Arg-Val-d-Pro-Pro-), shows antimicrobial activity against Gram-positive and -negative bacteria, but a much lower haemolytic activity and a much reduced ability to induce dye release from phosphatidylcholine/phosphatidylglycerol liposomes, when compared to PG-I. The enantiomeric form of the lead peptide shows comparable antimicrobial activity, a property shared with other cationic antimicrobial peptides acting on cell membranes. SAR studies involving the synthesis and biological profiling of over 100 single site substituted analogues, showed that the antimicrobial activity was tolerant to a large number of the substitutions tested. Some analogues showed slightly improved antimicrobial activities (2-4-fold lowering of MICs), whereas other substitutions caused large increases in haemolytic activity on human red blood cells.
Subject(s)
Antimicrobial Cationic Peptides/chemistry , Antimicrobial Cationic Peptides/pharmacology , Cations/chemistry , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Proteins/chemistry , Antimicrobial Cationic Peptides/chemical synthesis , Chromatography, High Pressure Liquid , Erythrocytes/drug effects , Hemolysis/drug effects , Humans , Molecular Structure , Peptides, Cyclic/chemical synthesis , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Macrocyclic peptidomimetics having a mixed peptide-peptoid backbone have been synthesized and shown to possess antibiotic activity against gram-positive and -negative bacteria with a low hemolytic activity against human erythrocytes; one is shown to adopt a regular beta-hairpin conformation by NMR in aqueous solution.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Peptides, Cyclic/chemical synthesis , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hemolysis/drug effects , Humans , Hydrogen Bonding , Kinetics , Magnetic Resonance Spectroscopy , Models, Molecular , Peptides, Cyclic/metabolism , Peptides, Cyclic/pharmacology , Protein Conformation , StereoisomerismABSTRACT
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.
