Stability and activity in sputum of G10KHc, a potent anti-Pseudomonas antimicrobial peptide.
G10KHc, a specifically targeted antimicrobial peptide developed in our laboratory, has shown rapid and selective killing activity against Pseudomonas aeruginosa in culture medium. Because of the major role played by this pathogen in cystic fibrosis, we sought to evaluate the utility of G10KHc under more physiologic conditions in vitro. In the current study, we found that robust G10KHc activity could be maintained in expectorated sputum if serine protease-dependent digestion associated with this fluid was inhibited, either by chemical antagonists or by the construction of a D-amino acid enantiomer of G10KHc. Further investigations revealed that specifically targeted antimicrobial peptide activity in sputum could be further enhanced when samples were treated with a combination of peptide and recombinant human DNase. Our results illustrate the importance of investigating combination therapy to treat cystic fibrosis, especially if protease-sensitive peptide-based agents, such as G10KHc, are to be developed as alternatives to, or in conjunction with, conventional small-molecule antibiotics.
Eckert
Randal
R
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
Mchardy
Ian
I
Yarbrough
Daniel K
DK
He
Jian
J
Qi
Fengxia
F
Anderson
Maxwell H
MH
Shi
Wenyuan
W
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004355:Drug Stability; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013183:Sputum / Q000382:microbiology
D000900:Anti-Bacterial Agents; C525842:G10KHc peptide; D010455:Peptides