title: Interaction of type A lantibiotics with undecaprenol-bound cell envelope precursors.
abstract: Lantibiotics are a unique group within the antimicrobial peptides characterized by the presence of thioether amino acids (lanthionine and methyllanthionine). These peptides are produced by and primarily act on Gram-positive bacteria exerting multiple activities at the cytoplasmic membrane of susceptible strains. Previously, the cell wall precursor lipid II was identified as the molecular target for the prototype lantibiotic nisin. Binding and sequestration of lipid II blocks the incorporation of the central cell wall precursor into the growing peptidoglycan network, thereby inhibiting the formation of a functional cell wall. Additionally, nisin combines this activity with a unique target-mediated pore formation, using lipid II as a docking molecule. The interaction with the pyrophosphate moiety of lipid II is crucial for nisin binding. We show that, besides binding to lipid II, nisin interacts with the lipid intermediates lipid III (undecaprenol-pyrophosphate-N-acetyl-glucosamine) and lipid IV (undecaprenol-pyrophosphate-N-acetyl-glucosamine-N-acetyl-mannosamine) of the wall teichoic acid (WTA) biosynthesis pathway. Binding of nisin to the precursors was observed at a stoichiometry of 2:1. The specific interaction with WTA precursors further promoted target-mediated pore formation in artificial lipid bilayers. Specific interactions with lipid III and lipid IV could also be demonstrated for related type A lantibiotics, for example, gallidermin, containing the conserved lipid-II-binding motif.
authors.affiliation: Pharmaceutical Microbiology Section, Institute of Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Müller
authors.forename: Hannah
authors.initials: H
authors.lastname: Ulm
authors.forename: Katrin
authors.initials: K
authors.lastname: Reder-Christ
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.forename: Tanja
authors.initials: T
authors.lastname: Schneider
mesh_terms: D020384:Acidic Glycosphingolipids / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001430:Bacteriocins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002473:Cell Wall / Q000737:chemistry; D002855:Chromatography, Thin Layer; D004926:Escherichia coli / Q000737:chemistry / Q000502:physiology; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D007778:Lactobacillus / Q000737:chemistry / Q000502:physiology; D008051:Lipid Bilayers; D008826:Microbial Sensitivity Tests; D016982:Micrococcus luteus / Q000187:drug effects / Q000254:growth & development; D009561:Nisin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010457:Peptidoglycan / Q000096:biosynthesis; D011485:Protein Binding; D013682:Teichoic Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013729:Terpenes / Q000378:metabolism; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D020384:Acidic Glycosphingolipids; D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D006028:Glycosphingolipids; D008051:Lipid Bilayers; C032403:Lipid III; C037242:Lipid IV; D010455:Peptides; D010457:Peptidoglycan; D013682:Teichoic Acids; D013729:Terpenes; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; C057656:gallidermin; D009561:Nisin; C017788:undecaprenol; C102526:nisin A