Crystal Structures of Two Vancomycin Complexes with Phosphate and N-Acetyl–d-Ala. Structural Comparison between Low-Affinity and High-Affinity Ligand Complexes of Vancomycin

Abstract

Crystal structures of two vancomycin complexes with phosphate and N-acetyl–d-Ala (AcDA) were determined. Each complex involves two crystallographically independent vancomycin molecules (V1 and V2) in the asymmetric unit, which form a usually observed back-to-back arranged vancomycin dimer V1–V2 with two disaccharide chains packed in a head-to-head manner, but only one of the two ligand-binding sites is occupied. Comparison of the published crystal structures of low-affinity (small in molecular size) ligand complexes of vancomycin with high-affinity (large) ligand complexes reveals that when the high-affinity ligand binds, three structural factors (hydrogen-bonding interactions between the two peptide-backbones and hydrophobic intra-dimer sugar–ring and ring (face)–ring (edge) interactions) work to enhance the stabilization of the back-to-back dimer-interface, an important factor that is believed to promote antibacterial activity. It has also been revealed, by examining the high-affinity ligand complexes (including N-acetyl–d-Ala–d-Ala), that sugar–ligand interaction could cause different affinities of the two halves of the dimer; this is a factor responsible for the failure of the ligand binding to V1 in the AcDA complex. Possible scenarios for the formation of vancomycin complexes with low-affinity as well as high-affinity ligands are presented.

Molecular Interactions between Glycopeptide Vancomycin and Bacterial Cell Wall Peptide Analogues

“…Aoki et al have reported the crystal structures of complexes formed between Van and peptides terminating with the sequence -d-Ala-d-Lac and have shown that hydrogen bonding interaction between phosphate ions and Van is non-negligible. [22] In neat water, Ac 2 KdAdL is able to replace solvent water found in the antibiotic binding pocket after both desolvation and conformational rearrangement of the binding site have taken place. [23] On the other hand, expulsion of HPO 4 2À and HEPES from the binding pocket is relatively more difficult due to their stronger interactions with Van.…”

“…[23] On the other hand, expulsion of HPO 4 2À and HEPES from the binding pocket is relatively more difficult due to their stronger interactions with Van. Based on recent crystal structure studies, [22,24] a simple model is proposed whereby a water-mediated hydrogen bond interaction between the amide nitrogen of the Lys residue in Ac 2 KdAdL and the oxygen of the terminal carboxylate group of Van is necessary to achieve favorable peptide orientation and energy to remove and replace HPO 4 2À and HEPES from the binding site. This results in a loose Ac 2 KdAdL-Van complex in buffer solution as compared to neat water.…”

Study of vancomycin derivatives on bio-conjugated activity and bio-optical imaging

“…After the cells were washed three times with PBS buffer to remove the unbound Van-porphyrins, the bacterial imaging was conducted upon the excitation of the Q bands of porphyrin under fluorescent microscope. 31 As shown in…”

“…With overuse of vancomycin in clinic, in company with that of related glycopeptide antibiotics in animal feeds, vancomycin-resistant Gram-positive bacteria have emerged. 31 The first vancomycin-resistant enterococci (VRE) strain was isolated from patients in an American hospital in 1987. 32 Since then, the prevalence of VRE strains have extended from the local to the global; The percentage of VRE reported among the bacterial infections sharply increased in decades 24,33…”

“…In our FCS measurement, the reduction in the binding strength between Van and bonding interaction between phosphate ions and Van is non-negligible. 31 In neat water, Ac 2 KDADL is able to replace solvent water found in the antibiotic binding pocket ATTENTION: The Singapore Copyright Act applies to the use of this document. Nanyang Technological University Library after both desolvation and conformational rearrangement of the binding site have taken place.…”