Strategies for the Discovery and Advancement of Novel Cationic Antimicrobial Peptides

E.      B. Hadley; R.      E.W. Hancock

Abstract

Multi-drug resistant bacteria are appearing at an alarming rate and impose significant burdens on healthcare systems worldwide. Cationic peptides have shown great promise as broad spectrum antimicrobial agents with a demonstrated ability to kill resistant bacteria, however, issues such as protease susceptibility and toxicity issues have delayed their clinical development. This review summarizes recent progress in the advancement of cationic antimicrobial peptides for the treatment of bacterial infections. The major focus of the discussion relates to recent advances in the areas of screening and in silico modeling. A selection of novel strategies that diverge from classical linear α-peptide antimicrobials is also discussed. A diverse array of candidate structures will be key to the ultimate development of a stable platform for clinical development. The ability to accurately predict peptide activity in silico and in a high-throughput manner should benefit all classes of cationic antimicrobial peptides and provide a larger set of candidate structures for clinical evaluation.

Keywords: Antimicrobial, Cationic, Peptide/kwd, >, QSAR, screening, in silico, Cationic Antimi-crobial Peptides, Multi-drug resistant, broad spectrum, protease susceptibility, Peptide, Gram negative bacteria, Pseudomonas aeruginosa, Gram-positive, innate immunity, structure activity relationships, host defense pep-tides, glycosaminoglycans, red blood cell hemolysis, lipopolysaccharides, teichoic, zwitterionic lipids, threshold level, nucleic acid synthesis, second-generation peptides, SPOT synthesis technique, luxCDABE-expressing Pseudo-monas aeuruginosa, Bac2a- and Bac2a-, EC50 values, artificial neural network, methicillin-resistant S. aureus, ana-phylatoxin peptide C3a., benchmark peptide LL37, lipids phosphatidylcholine, phosphatidylglycerol, dipiccolinic acid, linear -peptide antimicrobials, neurokinin derived peptides GKH17 and HKH17, PEGylation of peptides, Polymyxins, cationic cyclic lipopeptides, hydrophobic antibiotics, Peptide Mimics