Cheng Mu, Ziora Zyta M, Hansford Karl A, Blaskovich Mark A, Butler Mark S, Cooper Matthew A
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Org Biomol Chem. 2014 Apr 28;12(16):2568-75. 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 (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.
达巴万星是一种半合成糖肽，与万古霉素和替考拉宁相比具有增强的抗生素活性，它与脂联素II的C末端赖氨酰-D-丙氨酰-D-丙氨酸亚基结合，抑制肽聚糖生物合成。在本研究中，微量量热法和电喷雾电离（ESI）-质谱已被用于研究达巴万星的寡聚化与脂联素II肽模拟物二乙酰-Lys-D-Ala-D-Ala（Ac2-Kaa）结合之间的关系。达巴万星与配体结合时以反协同方式强烈二聚化，利托菌素A也是如此，但万古霉素和替考拉宁则不然。达巴万星和利托菌素A在配体结合时均采用“封闭”构象，这表明与配体结合的反协同二聚化可能是达巴万星/利托菌素A样糖肽的一个普遍特征。了解这些效应可能有助于深入了解具有协同配体结合和二聚化特性的新型达巴万星衍生物的设计，从而增强抗生素活性。
