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.
Highlights
Acute bacterial skin and skin-structure infections (ABSSSIs), which are commonly caused by the Gram-positive cocci Staphylococcus aureus, Streptococcus pyogenes and to a lesser extent Enterococcus faecalis and E. faecium,[1,2] lead to hospitalization and substantial health care costs.[3]
Telavancin and oritavancin are classified as vancomycin-type glycopeptides, while dalbavancin belongs to the teicoplanin-type class,[18] with an additional macrocyclic ring formed between aryl residues 1 and 3.19 The vancomycin-type glycopeptides, including vancomycin,[20] eremomycin,[21] balhimycin[22] and oritavancin,[23] are able to dimerise in aqueous solution with dimerisation being cooperative with ligand-binding.[20,21]
LC/MS analyses showed that dalbavancin was completely soluble and stable in this buffer (Fig. S2, see electrospray ionization (ESI)†), which was consistent with a previous study of dalbavancin solubility.[28]
Summary
Acute bacterial skin and skin-structure infections (ABSSSIs), which are commonly caused by the Gram-positive cocci Staphylococcus aureus, Streptococcus pyogenes and to a lesser extent Enterococcus faecalis and E. faecium,[1,2] lead to hospitalization and substantial health care costs.[3]. Dalbavancin dimerised strongly in an anti-cooperative manner with ligand-binding, as was the case for ristocetin A, but not for vancomycin and teicoplanin.
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