Lipid A and resistance of Salmonella typhimurium to antimicrobial granule proteins of human neutrophil granulocytes.
Granule extracts from human polymorphonuclear leukocytes were prepared and fractionated by chromatography on Sephadex G75-SF. One fraction exhibited potent antimicrobial activity against an Rd1 lipopolysaccharide (LPS) mutant of Salmonella typhimurium. Susceptibility of the mutant to antimicrobial activity appeared to be due to binding of granule proteins to lipid A because isolated native LPS succeeded in blocking the antimicrobial activity of granule extracts whereas base-hydrolyzed LPS failed to do so. Centrifugation of control and base-hydrolyzed LPS-protein mixtures in cesium chloride gradients suggested that only control LPS formed complexes with antimicrobial proteins. Further evidence that bactericidal proteins from polymorphonuclear leukocyte granules interact with lipid A was that sublethal concentrations of polymyxin B (an antibiotic known to bind to lipid A) rendered target bacteria phenotypically resistant to granule proteins. Moreover, a mutant of S. typhimurium which synthesized a lipid A with decreased electronegativity due to increased 4-amino-4-deoxy-L-arabinosylation at the 4'-phosphate exhibited increased resistance to both polymyxin B and granule proteins. These results suggest that polymyxin B and antimicrobial proteins derived from polymorphonuclear leukocyte granules interact with lipid A in an analogous manner.
D023181:Antimicrobial Cationic Peptides; D001667:Binding, Competitive; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000378:metabolism / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D006801:Humans; D008050:Lipid A / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides / Q000494:pharmacology; D011112:Polymyxin B / Q000378:metabolism / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000187:drug effects; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; C030509:neutrophil basic proteins; D011112:Polymyxin B