title: The designer proline-rich antibacterial peptide A3-APO is effective against systemic Escherichia coli infections in different mouse models.
abstract: Antimicrobial peptides are considered to be viable alternatives to conventional antibiotics. However, they rarely show systemic efficacy in animal models when added at non-toxic doses. The dimer A3-APO was designed to attack both the bacterial membrane and the Enterobacteriaceae-specific domain of the heat shock protein DnaK in order to reduce toxicity whilst maintaining activity. The peptide exhibited a minimal inhibitory concentration (MIC) range of 2-128 mg/L against 28 clinical Escherichia coli, Klebsiella pneumoniae and Salmonella enterica serovar Typhimurium strains, with a median MIC of 30 mg/L. At this concentration, A3-APO was bactericidal to E. coli 5770, a fluoroquinolone-resistant extended-spectrum beta-lactamase-producing strain. The No Observed Adverse Effect Limit (NOAEL) at repeated intraperitoneal peptide administration was 20mg/kg. When administered at this dose three times starting immediately after E. coli Neumann infection, A3-APO cured 100% of mice in a standard bacteraemia model used by the pharmaceutical industry. In a more stringent assay, when treatment started after E. coli 5770 bacteraemia had already been established, three doses of 10mg/kg A3-APO prolonged early survival at a rate similar to that of imipenem and reduced the bacterial counts to base level. When the second assay was repeated in kidney clearance conditions resembling those in humans, 10mg/kg A3-APO was as efficacious as imipenem in the long-term. The increased in vivo efficacy compared with the in vitro bactericidal figures can potentially be explained by the generally observable immunostimulatory properties of antimicrobial peptides. Peptide A3-APO shows promising features as a member in our antibiotic arsenal against multidrug-resistant bacterial pathogens.
authors.affiliation: Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary.
authors.forename: Dora
authors.initials: D
authors.lastname: Szabo
authors.forename: Eszter
authors.initials: E
authors.lastname: Ostorhazi
authors.forename: Annegret
authors.initials: A
authors.lastname: Binas
authors.forename: Ferenc
authors.initials: F
authors.lastname: Rozgonyi
authors.forename: Bela
authors.initials: B
authors.lastname: Kocsis
authors.forename: Marco
authors.initials: M
authors.lastname: Cassone
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Oliver
authors.initials: O
authors.lastname: Nolte
authors.forename: Laszlo
authors.initials: L
authors.lastname: Otvos
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy* / Q000517:prevention & control; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000517:prevention & control; D005260:Female; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D012486:Salmonella typhimurium / Q000187:drug effects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: C539766:A3-APO peptide; D000900:Anti-Bacterial Agents; D010455:Peptides