title: The functional association of polymyxin B with bacterial lipopolysaccharide is stereospecific: studies on polymyxin B nonapeptide.
abstract: The Gram-negative bacterial endotoxin lipopolysaccharide (LPS) is a major inducer of sepsis. The natural cyclic peptide polymyxin B (PMB) is a potent antimicrobial agent, albeit highly toxic, by virtue of its capacity to neutralize the devastating effects of LPS. However, the exact mode of association between PMB and LPS is not clear. In this study, we have synthesized polymyxin B nonapeptide, the LPS-binding cyclic domain of PMB, and its enantiomeric analogue and studied several parameters related to their interaction with LPS and their capacity to sensitize Gram-negative bacteria toward hydrophobic antibiotics. The results suggest that whereas the binding of the two enantiomeric peptides to E. coli and to E. coli LPS is rather similar, functional association with the bacterial cell is stereospecific. Thus, the L-enantiomer is capable of synergism with the hydrophobic antimicrobial drugs novobiocin and erythromycin, whereas the D-enantiomer is devoid of such activity. The potential of understanding and consequently utilizing the PMB-LPS association for novel, nontoxic PMB-derived drugs is discussed.
authors.affiliation: Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Tsubery
authors.forename: I
authors.initials: I
authors.lastname: Ofek
authors.forename: S
authors.initials: S
authors.lastname: Cohen
authors.forename: M
authors.initials: M
authors.lastname: Fridkin
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D004917:Erythromycin / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D008070:Lipopolysaccharides / Q000737:chemistry*; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D009675:Novobiocin / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D009842:Oligopeptides; D009675:Novobiocin; D004917:Erythromycin; C038934:polymyxin B nonapeptide; D011112:Polymyxin B