title: In vitro and in vivo activity of an antibacterial peptide analog against uropathogens.
abstract: The alarming rate of bacterial resistance induction highlights the clinical need for antimicrobial agents that act by novel modes of action. Based on the activity profile, the general tissue distribution and renal clearance of peptide-based drugs, we hypothesized that our newly developed pyrrhocoricin derivative would be able to fight resistant uropathogens in vitro and in vivo. Indeed, the Pip-pyrr-MeArg dimer killed all 11 urinary tract infection-related Escherichia coli and Klebsiella pneumoniae strains we studied in the sub-low micromolar concentration range. Almost all control antibiotics, including the currently leading trimethoprim-sulfametoxazole combination for urinary tract infection, remained without considerable activity against two or more of these bacterial strains. In a mouse ascending urinary tract infection model with E. coli CFT073 as pathogen, two doses of intravenous, subcutaneous or oral treatment with the Pip-pyrr-MeArg derivative reduced the bacterial counts in the kidneys, bladder and urine to varying levels. Statistically significant elimination or reduction of bacteria compared to untreated animals was observed at dual intravenous or subcutaneous doses of 0.4 or 10mg/kg, respectively. Serial passage of the same E. coli strain in the presence of sublethal doses of the designed peptide failed to generate resistant mutants. The Pip-pyrr-MeArg dimer showed no toxicity to COS-7 cells to the highest 500microM concentration studied.
authors.affiliation: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Mare
authors.initials: M
authors.lastname: Cudic
authors.forename: C Virginia
authors.initials: CV
authors.lastname: Lockatell
authors.forename: David E
authors.initials: DE
authors.lastname: Johnson
authors.forename: Laszlo
authors.initials: L
authors.lastname: Otvos
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D000892:Anti-Infective Agents, Urinary; D010455:Peptides