Direct interaction of a vancomycin derivative with bacterial enzymes involved in cell wall biosynthesis

Roy, Ranabir Sinha; Yang, Ping; Kodali, Srinivas; Xiong, Yusheng; Kim, Ronald M.; Griffin, Patrick R.; Ōnishi, Hiroshi; Kohler, Joyce; Silver, Lynn L.; Chapman, Kevin T.

doi:10.1016/s1074-5521(01)00075-8

Cited by 39 publications

(19 citation statements)

References 47 publications

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“…There was, notably, a significant difference in the sensitivities of telavancin and vancomycin to antagonism by dKAA in this assay. The IC 50 for vancomycin shifted greater than 10-fold in the presence of 0.5 mM dKAA, while the highest concentration of dKAA tested (40 mM) was required to increase the IC 50 for telavancin 10-fold ( Table 1). The antibacterial activity of telavancin, as measured by MIC determination, was more potent than that of vancomycin.…”

Section: Inhibition Of Macromolecular Biosynthesis In Intact Cellsmentioning

confidence: 99%

“…One proposed mechanism is that hydrophobic substituents of lipoglycopeptides confer strong dimerization and membrane-anchoring properties that allow for increased binding affinities for peptidoglycan intermediates at the target site in bacteria (1,3,4,9). The second proposed mechanism is that the liposaccharide elements of lipoglycopeptides interact directly with and inhibit transglycosylase enzymes that mediate the polymerization of precursors into immature, un-cross-linked peptidoglycan (16,23,24,30,50).…”

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confidence: 99%

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Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

Higgins

Chang

Debabov

et al. 2005

Antimicrob Agents Chemother

415

323

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The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited latestage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K ؉ . The timing of these changes correlated with rapid, concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.The emergence and spread of bacterial resistance to vancomycin, an important antibiotic used to treat serious infections caused by gram-positive bacteria, has prompted active research to discover new glycopeptides and semisynthetic analogs with improved antimicrobial properties. Vancomycin and related glycopeptide antibiotics inhibit cell wall synthesis in susceptible bacteria by binding with high specificity to peptidoglycan precursors containing the C-terminal D-alanyl-D-alanine (D-Ala-DAla) motif (8). The peptide portion of glycopeptide antibiotics forms a carboxylate binding pocket that imparts, through a combination of five hydrogen bonds plus favorable hydrophobic interactions, strong affinity for the D-Ala-D-Ala-containing terminus of lipid II (8,46,54). Rational approaches toward the design of glycopeptides with improved antimicrobial activities have been described previously (for reviews, see references 35 and 36). One promising approach has been the discovery of lipoglycopeptides, analogs containing hydrophobic groups substituted at the amine position of the disaccharide moiety (20,39,40,45).Telavancin, a semisynthetic derivative of vancomycin possessing a hydrophobic (decylaminoethyl) side chain appended to the vancosamine sugar and a hydrophilic [(phosphonomethyl)aminomethyl] group on the resorcinol-like 4Ј position of amino acid 7 (33), is in late-stage clinical development for the treatment of serious gram-positive infections. Telavancin and other lipoglycopeptides exhibit superior in vitro activity compa...

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Section: Inhibition Of Macromolecular Biosynthesis In Intact Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

Higgins

Chang

Debabov

et al. 2005

Antimicrob Agents Chemother

415

323

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“…These analogues were shown to inhibit the transglycosylation step of peptidoglycan biosynthesis, and we thus suggested that 2 and 5 interact directly with a component of the transglycosylation complex. Sinha Roy et al (8) provided support for this hypothesis recently when they showed that penicillin-binding protein 1b (PBP1b), the major transglycosylase in Escherichia coli, is retained on an affinity column derivatized with 2 or fragments thereof. We now report a study showing that 2 and 5 inhibit PBP1b by interacting directly with the enzyme (Fig.…”

mentioning

confidence: 98%

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

Chen

Walker

Sun

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

140

147

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Bacterial transglycosylases are enzymes that couple the disaccharide subunits of peptidoglycan to form long carbohydrate chains. These enzymes are the target of the pentasaccharide antibiotic moenomycin as well as the proposed target of certain glycopeptides that overcome vancomycin resistance. Because bacterial transglycosylases are difficult enzymes to study, it has not previously been possible to evaluate how moenomycin inhibits them or to determine whether glycopeptide analogues directly target them. We have identified transglycosylase assay conditions that enable kinetic analysis of inhibitors and have examined the inhibition of Escherichia coli penicillin-binding protein 1b (PBP1b) by moenomycin as well as by various glycopeptides. We report that chlorobiphenyl vancomycin analogues that are incapable of binding substrates nevertheless inhibit E. coli PBP1b, which shows that these compounds interact directly with the enzyme. These findings support the hypothesis that chlorobiphenyl vancomycin derivatives overcome vanA resistance by targeting bacterial transglycosylases. We have also found that moenomycin is not competitive with respect to the lipid II substrate of PBP1b, as has long been believed. With the development of suitable methods to evaluate bacterial transglycosylases, it is now possible to probe the mechanism of action of some potentially very important antibiotics.

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“…These observations suggest that the hydrophobic vancomycin derivatives inhibit transglycosylation independently of substrate binding, but probably by a mechanism in which they directly interact with the enzyme. It was possible to utilize this interaction in order to isolate PBPs from a crude mixture of E. coli membrane proteins by affinity chromatography, hydrophobic vancomycin derivatives being immobilized on solid support [85]. A second advantage of the semisynthetic hydrophobic glycopeptide derivatives, besides their activity against VRE, is their cellular response.…”

Section: Peptidoglycanmentioning

confidence: 99%

Carbohydrate‐Based Drug Discovery in the Battle against Bacterial Infections: New Opportunities Arising from Programmable One‐Pot Oligosaccharide Synthesis

Ritter¹,

Wong

2003

Carbohydrate‐Based Drug Discovery

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Direct interaction of a vancomycin derivative with bacterial enzymes involved in cell wall biosynthesis

Abstract: Hydrophobic vancomycins interact directly with a select subset of bacterial membrane proteins, suggesting the existence of discrete protein targets. Transglycosylase inhibition may play a role in the enhanced bioactivity of semisynthetic glycopeptides.

Cited by 39 publications

References 47 publications

Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

Carbohydrate‐Based Drug Discovery in the Battle against Bacterial Infections: New Opportunities Arising from Programmable One‐Pot Oligosaccharide Synthesis

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