Tight Binding of a Dimeric Derivative of Vancomycin with Dimeric <scp>l</scp>-Lys-<scp>d</scp>-Ala-<scp>d</scp>-Ala

Rao, Jianghong; Whitesides, George M.

doi:10.1021/ja971225l

Cited by 89 publications

(69 citation statements)

References 27 publications

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“…A dimer of vancomycin was synthesized following a procedure described in the literature [46] with some modification. In our procedure, BOP was used to catalyze the reaction, resulting in two products only-the desired covalent dimer and the linker-attached monomer.…”

Section: Synthesis Of Covalently Linked Vancomycin Dimer (V D )mentioning

confidence: 99%

Getting Closer to the Real Bacterial Cell Wall Target: Biomolecular Interactions of Water‐Soluble Lipid II with Glycopeptide Antibiotics

Vollmerhaus

Breukink

Heck

2003

Chemistry A European J

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A novel synthesized watersoluble variant of lipid II (LII) was used to evaluate the noncovalent interactions between a number of glycopeptide antibiotics and their receptor by bioaffinity electrospray ionization mass spectrometry (ESI-MS). The water-soluble variant of lipid II is an improved design, compared to the traditionally used tripeptide, of the target molecule on the bacterial cell wall. A representative group of glycopeptide antibiotics was selected for this study to evaluate the validity of the novel cell-wall-mimicking target LII. Structure ± function relationships of various glycopeptide antibiotics were investigated by means of 1) bioaffinity mass spectrometry to evaluate solution-phase molecular interactions with both LII and KAA, 2) fluorescence leakage experiments to study the interactions with the membrane-embedded lipid II, and 3) minimum inhibitory concentrations against the indicator strain Micrococcus flavus. Our results with the novel LII molecule reveal that some antibiotics interact differently with KAA and LII. Additionally, our data cast doubt on the hypothesis that antibiotic selfdimerization assists in the invivo efficacy. Finally, the water-soluble lipid II proved to be a better model of the bacterial cell wall.

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Section: Synthesis Of Covalently Linked Vancomycin Dimer (V D )mentioning

confidence: 99%

Getting Closer to the Real Bacterial Cell Wall Target: Biomolecular Interactions of Water‐Soluble Lipid II with Glycopeptide Antibiotics

Vollmerhaus

Breukink

Heck

2003

Chemistry A European J

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“…We calculated the value of We developed a competitive binding assay using ACE to determine the value of Kd of a dimeric derivative of Van, Van-%-Van, to a dimeric form of KDADA, L-R',-L ( Fig. 6 ; "d" in these structures indicates "dimer") [65]. In this (Fig.…”

Section: Determination Of the Binding Affinity Of Anti-dnp Rat Iggzb mentioning

confidence: 99%

Affinity capillary electrophoresis: A physical‐organic tool for studying interactions in biomolecular recognition

et al. 1998

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Affinity capillary electrophoresis (ACE) is a technique that is used to measure the binding affinity of receptors to neutral and charged ligands. ACE experiments are based on differences in the values of electrophoretic mobility of free and bound receptor. Scatchard analysis of the fraction of bound receptor, at equilibrium, as a function of the concentration of free ligand yields the dissociation constant of the receptor-ligand complex. ACE experiments are most conveniently performed on fused silica capillaries using a negatively charged receptor (molecular mass < 50 kDa) and increasing concentrations of a low molecular weight, charged ligand in the running buffer. ACE experiments that involve high molecular weight receptors may require the use of running buffers containing zwitterionic additives to prevent the receptors from adsorbing appreciably to the wall of the capillary. This review emphasizes ACE experiments performed with two model systems: bovine carbonic anhydrase II (BCA II) with arylsulfonamide ligands and vancomycin (Van), a glycopeptide antibiotic, with D-Ala-D-Ala (DADA)-based peptidyl ligands. Dissociation constants determined from ACE experiments performed with charged receptors and ligands can often be rationalized using electrostatic arguments. The combination of differently charged derivatives of proteins - protein charge ladders - and ACE is a physical-organic tool that is used to investigate electrostatic effects. Variations of ACE experiments have been used to estimate the charge of Van and of proteins in solution, and to determine the effect of the association of Van to Ac2KDADA on the value of pKa of its N-terminal amino group.

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“…Additionally, the Whitesides group constructed head-to-head dimers. [14] Perhaps, however, of more biological relevance are the head-to-tail dimers. Constructs of this type were synthesized by the Williams group, [15] linking from the C-terminus to the N-terminus, and by groups at Abbott [16] and Eli Lilly, [17] both bridging their monomeric units through the vancosamine nitrogen.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Vancomycin Dimers with Potent Activity against Vancomycin-Resistant Bacteria: Target-Accelerated Combinatorial Synthesis

et al. 2001

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Based on the notion that dimerization and/or variation of amino acid 1 of vancomycin could potentially enhance biological activity, a series of synthetic and chemical biology studies were undertaken in order to discover potent antibacterial agents. Herein we describe two ligation methods (disulfide formation and olefin metathesis) for dimerizing vancomycin derivatives and applications of target-accelerated combinatorial synthesis (e.g. combinatorial synthesis in the presence of vancomycin's target Ac2-L-Lys-D-Ala-D-Ala) to generate libraries of vancomycin dimers. Screening of these compound libraries led to the identification of a number of highly potent antibiotics effective against vancomycin-suspectible, vancomycin-intermediate resistant and, most significantly, vancomycin-resistant bacteria.

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Tight Binding of a Dimeric Derivative of Vancomycin with Dimeric l-Lys-d-Ala-d-Ala

Cited by 89 publications

References 27 publications

Getting Closer to the Real Bacterial Cell Wall Target: Biomolecular Interactions of Water‐Soluble Lipid II with Glycopeptide Antibiotics

Getting Closer to the Real Bacterial Cell Wall Target: Biomolecular Interactions of Water‐Soluble Lipid II with Glycopeptide Antibiotics

Affinity capillary electrophoresis: A physical‐organic tool for studying interactions in biomolecular recognition

Synthesis and Biological Evaluation of Vancomycin Dimers with Potent Activity against Vancomycin-Resistant Bacteria: Target-Accelerated Combinatorial Synthesis

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