Anti-cooperative ligand binding and dimerisation in the glycopeptide antibiotic dalbavancin

作者：Cheng Mu; Ziora Zyta M; Hansford Karl A; Blaskovich Mark A; Butler Mark S; Cooper Matthew A^*

来源：Organic and Biomolecular Chemistry, 2014, 12(16): 2568-2575.

DOI：10.1039/c3ob42428f

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 (Ac-2-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.

• 出版日期2014-4-28