Vancomycin: ligand recognition, dimerization and super‐complex formation

Abstract

The antibiotic vancomycin targets lipid II, blocking cell wall synthesis in Gram-positive bacteria. Despite extensive study, questions remain regarding how it recognizes its primary ligand and what is the most biologically relevant form of vancomycin. In this study, molecular dynamics simulation techniques have been used to examine the process of ligand binding and dimerization of vancomycin. Starting from one or more vancomycin monomers in solution, together with different peptide ligands derived from lipid II, the simulations predict the structures of the ligated monomeric and dimeric complexes to within 0.1 nm rmsd of the structures determined experimentally. The simulations reproduce the conformation transitions observed by NMR and suggest that proposed differences between the crystal structure and the solution structure are an artifact of the way the NMR data has been interpreted in terms of a structural model. The spontaneous formation of both back-to-back and face-to-face dimers was observed in the simulations. This has allowed a detailed analysis of the origin of the cooperatively between ligand binding and dimerization and suggests that the formation of face-to-face dimers could be functionally significant. The work also highlights the possible role of structural water in stabilizing the vancomycin ligand complex and its role in the manifestation of vancomycin resistance.

Affinities and in-plane stress forces between glycopeptide antibiotics and biomimetic bacterial membranes

“…In SPR studies, the binding of vancomycin to the control surfaces was much weaker than that to doc-KAA surfaces, consistent with previous observations that vancomycin specifically binds to the bacterial cell wall precursor lipid II, rather than to phospholipid layers [9,28,33]. Teicoplanin binds to membranes in the absence of doc-KAA, due to the lipophilic C 11 acyl chain, which can serve as a membrane anchor to localize the antibiotic in the membrane [34,35].…”

“…In the presence of doc-KAA, the binding of teicoplanin was also enhanced; attributed to cooperative binding of precursors analogues binding and membrane anchoring [10]. This explains why teicoplanin at lower concentrations also showed significant responses, whereas significant binding for vancomycin is only observed when concentrations are sufficient to lead to a dimer population at the membrane surface [33][34][35]37].…”

Association of vancomycin with lipid vesicles

“…To this end, a further investigation of vancomycin structure and bacterial membrane composition is required. In addition, self [20,21] and ligand-induced dimerization [26,27] of vancomycin might also play an important role as a larger hydrophobic interface once shielded by dimeric interaction has to be covered by membrane association.…”

“…Based on the K a value derived from data fitting, binding affinity of vancomycin to POPG is significantly higher than that to POPE and CL (Figure 4), suggesting that POPG is the major contributor to the association of vancomycin with liposome. The observation could be explained by careful examination of the structure of vancomycin [20,21] and the lipids (Figure 4). Positive charged amine in the head group of POPE does not appear to favour the interaction with uncharged vancomycin.…”

Development and In Vitro Evaluation of a Novel Drug Delivery System (Albumin Microspheres Containing Liposomes) Applied to Vancomycin

“…However, the data in the literature support the ability of this molecule to selfassemble and form supramolecular structures in a liganddependent manner. 33,34 Because vancomycin is a diprotic solute (pKa ¼ 2.99 and pKa ¼ 9.93), the acidic pH might help to cause vancomycin self-assembly and the formation of oligomeric crystalline vancomycin structures. As previously commented, pH also affects albumin conformation, the expanded form at acid pH likely facilitating its role as a ligand molecule.…”