title: Effect of size and N-terminal residue characteristics on bacterial cell penetration and antibacterial activity of the proline-rich peptide Bac7.
abstract: Bac7 is a proline-rich antimicrobial peptide, selective for Gram-negative bacteria, which acts intracellularly after membrane translocation. Progressively shortened fragments of Bac7 allowed determining the minimal sequence required for entry and antimicrobial activity as a 16-residue, N-terminal fragment, while further shortening led to a marked decrease in both functions. Furthermore, two N-terminal arginine residues were required for efficient translocation and activity. Analogues in which these residues were omitted, or where the side chain steric or physicochemical characteristics were systematically altered, were tested on different Escherichia coli strains, including a mutant with a destabilized outer membrane and one lacking the relevant SbmA membrane transport protein. H-bonding capacity, stereochemistry, and charge, in that order, played a determining role for efficient transit through both the outer and cytoplasmic membranes. Our studies allowed building a more detailed model for the mode-of-action of Bac7, and confirming its potential as an anti-infective agent, also suggesting it may be a vehicle for internalization of other antibiotic cargo.
authors.affiliation: Department of Life Sciences and §Department of Chemical & Pharmaceutical Sciences, University of Trieste , Trieste I-34127, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Guida
authors.forename: Monica
authors.initials: M
authors.lastname: Benincasa
authors.forename: Sotir
authors.initials: S
authors.lastname: Zahariev
authors.forename: Marco
authors.initials: M
authors.lastname: Scocchi
authors.forename: Federico
authors.initials: F
authors.lastname: Berti
authors.forename: Renato
authors.initials: R
authors.lastname: Gennaro
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tossi
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009010:Monte Carlo Method; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; C056454:bactenecin