title: Anti-cooperative ligand binding and dimerisation in the glycopeptide antibiotic dalbavancin.
abstract: Dalbavancin, a semi-synthetic glycopeptide with enhanced antibiotic activity compared to vancomycin and teicoplanin, binds to the C-terminal lysyl-d-alanyl-d-alanine subunit of Lipid II, inhibiting peptidoglycan biosynthesis. In this study, micro-calorimetry and electrospray ionization (ESI)-MS have been used to investigate the relationship between oligomerisation of dalbavancin and binding of a Lipid II peptide mimic, diacetyl-Lys-d-Ala-d-Ala (Ac2-Kaa). Dalbavancin dimerised strongly in an anti-cooperative manner with ligand-binding, as was the case for ristocetin A, but not for vancomycin and teicoplanin. Dalbavancin and ristocetin A both adopt an 'closed' conformation upon ligand binding, suggesting anti-cooperative dimerisation with ligand-binding may be a general feature of dalbavancin/ristocetin A-like glycopeptides. Understanding these effects may provide insight into design of novel dalbavancin derivatives with cooperative ligand-binding and dimerisation characteristics that could enhance antibiotic activity.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. m.cooper@uq.edu.au.
authors.forename: Mu
authors.initials: M
authors.lastname: Cheng
authors.forename: Zyta M
authors.initials: ZM
authors.lastname: Ziora
authors.forename: Karl A
authors.initials: KA
authors.lastname: Hansford
authors.forename: Mark A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: Mark S
authors.initials: MS
authors.lastname: Butler
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry; D019281:Dimerization; D006020:Glycopeptides / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D012310:Ristocetin / Q000737:chemistry; D012996:Solutions; D021241:Spectrometry, Mass, Electrospray Ionization; D017334:Teicoplanin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D008024:Ligands; D012996:Solutions; D012310:Ristocetin; C016719:ristocetin A; D017334:Teicoplanin; C469289:dalbavancin