title: Tailoring an antibacterial peptide of human lysosomal cathepsin G to enhance its broad-spectrum action against antibiotic-resistant bacterial pathogens.
abstract: Neutrophils contain several cationic antimicrobial proteins or peptides (CAPs) that exert antibiotic-like action against bacteria. These host-derived antibiotics kill susceptible bacteria by oxygen-independent mechanisms. Considerable interest in their activity has been generated in recent years due not only to their likely important role in innate host defense against infection, but also their possible use as therapeutic agents in treating infections caused by antibiotic-resistant pathogens. We have studied the antibacterial properties of human lysosomal cathepsin G (cat G). This highly cationic serine protease contains at least three antibacterial regions that by themselves can exert antibacterial action against Gram-negative bacteria, such as Pseudomonas aeruginosa. Only one of these peptides, defined by residues 117-136 of full-length cat G, has bactericidal action against Gram-positive pathogens, such as Staphylococcus aureus. Due to the broad-spectrum antibacterial action of this peptide, we have sought to define the amino acids within its primary sequence required for this activity and have developed variants with improved activity. This review emphasizes the importance of both cationicity and hydrophobicity as necessary characteristics for the antibacterial action of CAPs. It also proposes the strategy that naturally occurring large human CAPs can be dissected to smaller CAPs and then modified to enhance their activity in vitro. This approach could prove beneficial to those interested in developing antimicrobial peptides as therapeutic agents.
authors.affiliation: Laboratories of Bacterial Pathogenesis, Research Service, The VA Medical Center, Decatur, GA 30033, USA. wshafer@emory.edu
authors.forename: W M
authors.initials: WM
authors.lastname: Shafer
authors.forename: S
authors.initials: S
authors.lastname: Katzif
authors.forename: S
authors.initials: S
authors.lastname: Bowers
authors.forename: M
authors.initials: M
authors.lastname: Fallon
authors.forename: M
authors.initials: M
authors.lastname: Hubalek
authors.forename: M S
authors.initials: MS
authors.lastname: Reed
authors.forename: P
authors.initials: P
authors.lastname: Veprek
authors.forename: J
authors.initials: J
authors.lastname: Pohl
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D056649:Cathepsin G; D002403:Cathepsins / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006801:Humans; D008247:Lysosomes / Q000737:chemistry / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000737:chemistry / Q000201:enzymology / Q000648:ultrastructure; D012697:Serine Endopeptidases; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G