Penicillin-binding protein inactivation by human neutrophil myeloperoxidase.
Myeloperoxidase (MPO), H2O2, and chloride comprise a potent antimicrobial system believed to contribute to the antimicrobial functions of neutrophils and monocytes. The mechanisms of microbicidal action are complex and not fully defined. This report describes the MPO-mediated inactivation, in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, of a class of cytoplasmic membrane enzymes (penicillin-binding proteins, PBPs) found in all eubacteria, that covalently bind beta-lactam antibiotics to their active sites with loss of enzymatic activity. Inactivation of "essential" PBPs, including PBP1-PBP3 of E. coli, leads to unbalanced bacterial growth and cell death. MPO treatment of bacteria was associated with loss of penicillin binding by PBPs, strongly suggesting PBP inactivation. In E. coli, PBP inactivation was most rapid with PBP3, where the rate of decline in binding activity approximated but did not equal loss of viability. Changes in E. coli morphology (elongation), observed just before bacteriolysis, were consistent with early predominant inactivation of PBP3. We conclude that inactivation of essential PBPs is sufficient to account for an important fraction of MPO-mediated bacterial action. This feature of MPO action interestingly recapitulates an antibacterial strategy evolved by beta-lactam-producing molds that must compete with bacteria for limited ecologic niches.
Rakita
R M
RM
Department of Medicine, University of Washington, Seattle 98195.
Rosen
H
H
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006602:Hexosyltransferases; D006801:Humans; D007769:Lactams; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology*; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D009195:Peroxidase / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D007769:Lactams; D046915:Penicillin-Binding Proteins; D009195:Peroxidase; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase