Mode of Action of Van-M-02, a Novel Glycopeptide Inhibitor of Peptidoglycan Synthesis, in Vancomycin-Resistant Bacteria

Miura, Kenji; Yamashiro, Hidenori; Uotani, Kouichi; Kojima, Satoshi; Yutsudo, Takashi; Lu, Jiaheng; Yoshida, Osamu; Yamano, Yoshinori; Maki, Hideki; Arimoto, Hirokazu

doi:10.1128/aac.00927-09

Cited by 11 publications

(20 citation statements)

References 10 publications

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“…These depsi-lipid intermediates are common to VRSA and vancomycin-resistant enterococci (VRE). Although, as previously reported, 12 isolation of cell-wall precursors in the early stage of the biosynthesis of peptidoglycan is possible, all precursors are lipidated with undecaprenyl-pyrophosphate (C55) in the late stage of the synthesis of peptidoglycan. Purification of these cell-wall precursors from natural resources has been proven to be difficult (even for wild-type lipid intermediates), 16 and chemical synthesis is currently the only way to obtain these precursors.…”

Section: Resultsmentioning

confidence: 78%

“…We have recently reported a cell-free assay that reconstitutes the late stage of the biosynthesis of peptidoglycan in vancomycin-resistant S. aureus (VRSA). 12 …”

Section: Introductionmentioning

confidence: 99%

“…It provides nascent peptidoglycan from UDP-Mur N Ac-pentapeptide (vancomycin-susceptible model; UDP=uridine diphosphate, Mur N Ac= N -acetylmuramic acid) or UDP-Mur N Ac-pentadepsipeptide (resistant model). The modes of action of the vancomycin derivatives were analyzed by using this assay, and differences were successfully shown for a lipoglycopeptide 12 and vancomycin dimers in the resistant model. 13 However, a limitation of this assay is that inhibition by antibacterials is provided as a general effect without information on the specific action at each enzymatic step.…”

Section: Introductionmentioning

confidence: 99%

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Staphylococcus aureus Penicillin‐Binding Protein 2 Can Use Depsi‐Lipid II Derived from Vancomycin‐Resistant Strains for Cell Wall Synthesis

Nakamura

Yamashiro

Miya

et al. 2013

Chemistry A European J

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Vancomycin-resistant Staphylococcus aureus (S. aureus) (VRSA) uses depsipeptide-containing modified cell-wall precursors for the biosynthesis of peptidoglycan. Transglycosylase is responsible for the polymerization of the peptidoglycan, and the penicillin-binding protein 2 (PBP2) plays a major role in the polymerization among several transglycosylases of wild-type S. aureus. However, it is unclear whether VRSA processes the depsipeptide-containing peptidoglycan precursor by using PBP2. Here, we describe the total synthesis of depsi-lipid I, a cell-wall precursor of VRSA. By using this chemistry, we prepared a depsi-lipid II analogue as substrate for a cell-free transglycosylation system. The reconstituted system revealed that the PBP2 of S. aureus is able to process a depsi-lipid II intermediate as efficiently as its normal substrate. Moreover, the system was successfully used to demonstrate the difference in the mode of action of the two antibiotics moenomycin and vancomycin.

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Section: Resultsmentioning

confidence: 78%

“…We have recently reported a cell-free assay that reconstitutes the late stage of the biosynthesis of peptidoglycan in vancomycin-resistant S. aureus (VRSA). 12 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Staphylococcus aureus Penicillin‐Binding Protein 2 Can Use Depsi‐Lipid II Derived from Vancomycin‐Resistant Strains for Cell Wall Synthesis

Nakamura

Yamashiro

Miya

et al. 2013

Chemistry A European J

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“…1), N-terminal-degraded Van-M-02 was synthesized in order to assess the contribution of the D-alanyl-D-alanine binding pocket to the activity of Van-M-02. 37) Dimer 1 and Dimer 2 ( Fig. 1) synthesized as vancomycin dimers exhibit strong activity against vancomycin-resistant bacteria.…”

Section: Kinetic Parameters and Sensorgrams Of Antimicrobial Agents Fmentioning

confidence: 96%

“…17) Various vancomycin analogs have been synthesized and their antimicrobial activities have been estimated and characterized. [37][38][39][40] Van-M-02 (Fig. 1), synthesized as a glycopeptide inhibitor of peptidoglycan synthesis, has activities against Gram-positive bacteria including VRE.…”

Section: Kinetic Parameters and Sensorgrams Of Antimicrobial Agents Fmentioning

confidence: 99%

Binding Properties of Antimicrobial Agents to Lipid Membranes Using Surface Plasmon Resonance

Kinouchi

Arimoto

Nishiguchi

et al. 2014

Biological & Pharmaceutical Bulletin

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In the present study, we examined the interaction of antimicrobial agents with four model lipid membranes that mimicked mammalian cell membranes and Gram-positive and -negative bacterial membranes and analyzed the binding kinetics using our surface plasmon resonance (SPR) technique. The selective and specific binding characteristics of antimicrobial agents to the lipid membranes were estimated, and the kinetic parameters were analyzed by application of a two-state reaction model. Reproducible analysis of binding kinetics was observed. Vancomyicn, teicoplanin, erythromycin, and linezolid showed little interaction with the four lipid membranes in the SPR system. On the other hand, vancomycin analogues showed interaction with the model lipid membranes in the SPR system. The selective and specific binding characteristics of vancomycin analogues to the lipid membranes are discussed based on data for in vitro antibacterial activities and our data on the binding affinity of the D-alanyl-D-alanine terminus of a pentapeptide cell wall obtained by SPR. The mechanism of antibacterial activity against Staphylococcus aureus and vancomycin-resistant enterococci could be evaluated using the binding affinity obtained with our SPR techniques. The results indicate that the SPR method could be widely applied to predict binding characteristics, such as selectivity and specificity, of many antimicrobial agents to lipid membranes. Key words surface plasmon resonance; lipid membrane; antimicrobial agent; vancomycinThe properties and mechanisms of drug interactions with biological membranes serve as critical information in the drug discovery stage to characterize the pharmacokinetics and pharmacodynamics properties of drug candidates. In particular, the affinity of antimicrobial agents for lipid membranes is one of the critical factors influencing their selectivity and potency and plays an important role in the antimicrobial mechanism of action.1-7) In order to accelerate drug discovery and development, various in vitro analytical techniques, such as circular dichroism spectroscopy, fluorescence spectroscopy, differential scanning calorimetry, nuclear magnetic resonance, and fluorescence resonance energy transfer, have been employed. [8][9][10]

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Elucidation of the Active Conformation of Vancomycin Dimers with Antibacterial Activity against Vancomycin‐Resistant Bacteria

Nakamura

Yamashiro

Hayashi

et al. 2012

Chemistry A European J

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Covalently linked vancomycin dimers have attracted a great deal of attention among researchers because of their enhanced antibacterial activity against vancomycin-resistant strains. However, the lack of a clear insight into the mechanisms of action of these dimers hampers rational optimization of their antibacterial potency. Here, we describe the synthesis and antibacterial activity of novel vancomycin dimers with a constrained molecular conformation achieved by two tethers between vancomycin units. Conformational restriction is a useful strategy for studying the relationship between the molecular topology and biological activity of compounds. In this study, two vancomycin units were linked at three distinct positions of the glycopeptide (vancosamine residue (V), C terminus (C), and N terminus (N)) to form two types of novel vancomycin cyclic dimers. Active NC-VV-linked dimers with a stable conformation as indicated by molecular mechanics calculations selectively suppressed the peptidoglycan polymerization reaction of vancomycin-resistant Staphylococcus aureus in vitro. In addition, double-disk diffusion tests indicated that the antibacterial activity of these dimers against vancomycin-resistant enterococci might arise from the inhibition of enzymes responsible for peptidoglycan polymerization. These findings provide a new insight into the biological targets of vancomycin dimers and the conformational requirements for efficient antibacterial activity against vancomycin-resistant strains.

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Mode of Action of Van-M-02, a Novel Glycopeptide Inhibitor of Peptidoglycan Synthesis, in Vancomycin-Resistant Bacteria

Cited by 11 publications

References 10 publications

Staphylococcus aureus Penicillin‐Binding Protein 2 Can Use Depsi‐Lipid II Derived from Vancomycin‐Resistant Strains for Cell Wall Synthesis

Staphylococcus aureus Penicillin‐Binding Protein 2 Can Use Depsi‐Lipid II Derived from Vancomycin‐Resistant Strains for Cell Wall Synthesis

Binding Properties of Antimicrobial Agents to Lipid Membranes Using Surface Plasmon Resonance

Elucidation of the Active Conformation of Vancomycin Dimers with Antibacterial Activity against Vancomycin‐Resistant Bacteria

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