Bactericidal activities of synthetic human leukocyte cathepsin G-derived antibiotic peptides and congeners against Actinobacillus actinomycetemcomitans and Capnocytophaga sputigena.
Actinobacillus actinomycetemcomitans and Capnocytophaga spp. are gram-negative bacteria implicated in the etiology of periodontal disease (particularly in individuals with neutrophil defects) and life-threatening systemic infections. They are resistant to many antibiotics of microbial origin but are sensitive to the nonoxidative microbicidal action of neutrophils. These organisms are susceptible to the microbicidal effect of cathepsin G but are killed by two distinct mechanisms. The purpose of this study was to assess their sensitivity to the antibiotic effects of IIGGR and HPQYNQR, antimicrobial peptides derived from human neutrophil cathepsin G. The efficacies of the synthetic peptides IIGGR and HPQYNQR were tested by single-dose screening, dose-response, and kinetic assays against three representative strains (each) of A. actinomycetemcomitans and Capnocytophaga spp. and one strain of Eikenella corrodens. Strains of A. actinomycetemcomitans were sensitive to IIGGR and HPQYNQR at equal concentrations (wt/vol), whereas strains of Capnocytophaga and E. corrodens were more sensitive to IIGGR than to HPQYNQR. These differential antibiotic effects occurred over both time and dose ranges too narrow to be of therapeutic significance but are consistent with the premise that cathepsin G kills these oral bacteria by two distinct mechanisms. Except for IVGGR, congeners of IIGGR, including AIGGR, IAGGR, IIAGR, IIGAR, IIGGA, IQGGR, ILGGR, and I-norleucyl-GGR (InLGGR), were microbicidal at 500 micrograms/ml. IIGGR-amide exhibited no antibiotic activity. The D-enantiomer of IIGGR, DIDIGGDR, was as potent as IIGGR itself. APQYNQR exhibited antibiotic activity but somewhat less than HPQYNQR. We conclude that charge distribution, but not chirality or net charge, is an important determinant in the antibiotic efficacy of IIGGR. Moreover, peptide antibiotics derived from cathepsin G may have therapeutic value against periodontal gram-negative, facultative bacteria.
Miyasaki
K T
KT
School of Dentistry, University of California, Los Angeles 90024.
Bodeau
A L
AL
Pohl
J
J
Shafer
W M
WM
D000189:Actinobacillus Infections / Q000188:drug therapy / Q000382:microbiology; D016976:Aggregatibacter actinomycetemcomitans / Q000187:drug effects*; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002206:Capnocytophaga / Q000187:drug effects*; D056649:Cathepsin G; D002403:Cathepsins / Q000737:chemistry / Q000494:pharmacology*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D010532:Peritoneal Diseases / Q000188:drug therapy / Q000382:microbiology; D012697:Serine Endopeptidases
D000900:Anti-Bacterial Agents; D010446:Peptide Fragments; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G