Effects of intratracheal administration of novispirin G10 on a rat model of mucoid Pseudomonas aeruginosa lung infection

Zhijun Song, Hong Wu, Per Mygind, Dora Raventos, Carsten Sonksen, Hans-Henrik Kristensen, Niels Høiby

Abstract

Chronic Pseudomonas aeruginosa lung infection is a major problem for patients with cystic fibrosis (CF). The biofilm mode of growth of the pathogen makes it highly resistant to antibiotic treatment, and this is especially pronounced with mucoid strains. In this study, novispirin G10, a synthetic antimicrobial peptide patterned loosely on sheep myeloid antimicrobial peptide 29, was tested in a rat model of mucoid P. aeruginosa lung infection. P. aeruginosa NH57388A, a mucoid strain isolated from a CF patient, was mixed with the alginate produced by the bacterium itself and adjusted to a concentration of 10(10) CFU/ml. Each rat received 10(9) CFU of bacteria intratracheally in the left lung to establish lung infection. At 0 and 3 h post P. aeruginosa infection, the treated group of rats received novispirin G10 (0.1 mg/ml, 0.1 ml/rat) intratracheally, whereas the control group received vehicle treatment only. The animals were sacrificed on days 3, 5, 7, and 10 after challenge for evaluation of various parameters. On day 5, 50% of the rats in the treated group had cleared the bacteria from the lungs, whereas in the control group, none of the rats cleared the pathogen (P < 0.03). The average bacterial loads remaining in the lungs of treated rats on days 3 and 5 were more than 170- and 330-fold lower than in the control groups (P < 0.0005 and P < 0.0003). In accordance, the macroscopic and microscopic lung pathology was also significantly milder in the treated group compared to the control group (P < 0.0002). Lung cytokine responses in the treated group were significantly lower than in the control group. The results suggest that novispirin G10 might be useful in treating antibiotic-resistant P. aeruginosa lung infections.

Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
Volume49
Issue number9
Pages (from-to)3868-74
Number of pages7
ISSN0066-4804
DOIs
Publication statusPublished - Sept 2005
Externally publishedYes

Keywords

  • Animals
  • Anti-Bacterial Agents/administration & dosage
  • Antimicrobial Cationic Peptides/administration & dosage
  • Cloning, Molecular
  • Colony Count, Microbial
  • Cystic Fibrosis/microbiology
  • Cytokines/biosynthesis
  • Escherichia coli/metabolism
  • Female
  • Intubation, Intratracheal
  • Lung/metabolism
  • Lung Diseases/drug therapy
  • Microbial Sensitivity Tests
  • Pseudomonas Infections/drug therapy
  • Pseudomonas aeruginosa/drug effects
  • Rats
  • Rats, Inbred Lew
  • Recombinant Proteins/biosynthesis
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

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