title: Semisynthetic Lipopeptides Derived from Nisin Display Antibacterial Activity and Lipid II Binding on Par with That of the Parent Compound.
abstract: The lipid II-binding N-terminus of nisin, comprising the so-called A/B ring system, was synthetically modified to provide antibacterially active and proteolytically stable derivatives. A variety of lipids were coupled to the C-terminus of the nisin A/B ring system to generate semisynthetic constructs that display potent inhibition of bacterial growth, with activities approaching that of nisin itself. Most notable was the activity observed against clinically relevant bacterial strains including MRSA and VRE. Experiments with membrane models indicate that these constructs operate via a lipid II-mediated mode of action without causing pore formation. A lipid II-dependent mechanism of action is further supported by antagonization assays wherein the addition of lipid II was found to effectively block the antibacterial activity of the nisin-derived lipopeptides.
authors.forename: Timo
authors.initials: T
authors.lastname: Koopmans
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wood
authors.forename: Peter
authors.initials: P
authors.lastname: 't Hart
authors.forename: Laurens H J
authors.initials: LH
authors.lastname: Kleijn
authors.affiliation: ‡Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Antoni P A
authors.initials: AP
authors.lastname: Hendrickx
authors.affiliation: ‡Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Rob J L
authors.initials: RJ
authors.lastname: Willems
authors.affiliation: §Membrane Biochemistry and Biophysics Group, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.forename: Nathaniel I
authors.initials: NI
authors.lastname: Martin
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004355:Drug Stability; D016984:Enterococcus faecium / Q000187:drug effects; D006801:Humans; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009561:Nisin / Q000737:chemistry*; D059748:Proteolysis; D053835:Unilamellar Liposomes / Q000378:metabolism; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D055666:Lipopeptides; D053835:Unilamellar Liposomes; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D009561:Nisin