Antimicrobial peptide therapeutics for cystic fibrosis.
Greater than 90% of lung infections in cystic fibrosis (CF) patients are caused by Pseudomonas aeruginosa, and the majority of these patients subsequently die from lung damage. Current therapies are either targeted at reducing obstruction, reducing inflammation, or reducing infection. To identify potential therapeutic agents for the CF lung, 150 antimicrobial peptides consisting of three distinct structural classes were screened against mucoid and multidrug-resistant clinical isolates of P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Staphylococcus aureus. Five peptides that retained potent antimicrobial activities in physiological salt and divalent cation environment were further characterized in vivo using a rat chronic lung infection model. All animals were inoculated intratracheally with 10(4) P. aeruginosa mucoid PAO1 cells in agar beads. Three days following inoculation treatment was initiated. Animals were treated daily for 3 days with 100 microl of peptide solution (1 mg/ml) in 10 mM sodium citrate, which was deposited via either intratracheal instillation or aerosolization. Control animals received daily exposure to vehicle alone. At the end of the treatment the lungs of the animals were removed for quantitative culture. Four peptides, HBCM2, HBCM3, HBCPalpha-2, and HB71, demonstrated significant reduction in Pseudomonas bioburden in the lung of rats. Further in vivo studies provided direct evidence that anti-inflammatory activity was associated with three of these peptides. Therefore, small bioactive peptides have the potential to attack two of the components responsible for the progression of lung damage in the CF disease: infection and inflammation.
Helix Biomedix Inc., 22122 20th Ave. SE, Bothell, Washington 98021, USA. lzhang@helixbiomedix.com
Lijuan
L
Zhang
Jody
J
Parente
Scott M
SM
Harris
Donald E
DE
Woods
Robert E W
RE
Hancock
Timothy J
TJ
Falla
D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000382:microbiology*; D004195:Disease Models, Animal; D004427:Ear Diseases / Q000188:drug therapy; D004487:Edema / Q000188:drug therapy; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy* / Q000382:microbiology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D051381:Rats; D013211:Staphylococcus aureus / Q000187:drug effects
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides