title: Getting closer to the real bacterial cell wall target: biomolecular interactions of water-soluble lipid II with glycopeptide antibiotics.
abstract: A novel synthesized water-soluble variant of lipid II (LII) was used to evaluate the noncovalent interactions between a number of glycopeptide antibiotics and their receptor by bioaffinity electrospray ionization mass spectrometry (ESI-MS). The water-soluble variant of lipid II is an improved design, compared to the traditionally used tripeptide N,N'-diacetyl-L-lysyl-D-alanyl-D-alanine (KAA), of the target molecule on the bacterial cell wall. A representative group of glycopeptide antibiotics was selected for this study to evaluate the validity of the novel cell-wall-mimicking target LII. Structure-function relationships of various glycopeptide antibiotics were investigated by means of 1) bioaffinity mass spectrometry to evaluate solution-phase molecular interactions with both LII and KAA, 2) fluorescence leakage experiments to study the interactions with the membrane-embedded lipid II, and 3) minimum inhibitory concentrations against the indicator strain Micrococcus flavus. Our results with the novel LII molecule reveal that some antibiotics interact differently with KAA and LII. Additionally, our data cast doubt on the hypothesis that antibiotic selfdimerization assists in the in-vivo efficacy. Finally, the water-soluble lipid II proved to be a better model of the bacterial cell wall.
authors.affiliation: Department of Biomolecular Mass Spectrometry, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, The Netherlands.
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: Vollmerhaus
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002473:Cell Wall / Q000737:chemistry / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D008837:Micrococcus / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D018716:Molecular Mimicry; D011485:Protein Binding; D012310:Ristocetin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013329:Structure-Activity Relationship; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000737:chemistry / Q000378:metabolism; D014640:Vancomycin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D008055:Lipids; D014538:Uridine Diphosphate N-Acetylmuramic Acid; D014867:Water; D012310:Ristocetin; D014640:Vancomycin