The Role of Hydrophobic Substituents in the Biological Activityof Glycopeptide Antibiotics

Kerns, Robert J.; Dong, Steven D.; Fukuzawa, Seketsu; Carbeck, Jeffrey D.; Kohler, Joyce; Silver, Lynn L.; Kahne, Daniel

doi:10.1021/ja0027665

Cited by 105 publications

(100 citation statements)

References 10 publications

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“…We have previously made many glycopeptide derivatives containing lipid substituents at different positions, either on the aglycone or on the carbohydrates (7,(33)(34)(35)(36). We have found that the potency of most lipid-linked glycopeptides decreases dramatically when their peptide-binding pockets are damaged, implying that peptide binding is important for activity.…”

Section: Discussionmentioning

confidence: 99%

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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.

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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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Section: Discussionmentioning

confidence: 99%

“…However, a small subset of lipid-linked glycopeptides retain good activity against both vanA and vanB strains when their binding pockets are damaged. Activity against vanA strains requires specific positioning of a hydrophobic substituent attached to the vancomycin disaccharide (7,34,36).…”

Section: Discussionmentioning

confidence: 99%

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.

Self Cite

140

147

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“…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).The aim of the present study was to investigate the molecular mechanism of antibacterial action of telavancin. We provide evidence that telavancin possesses at least two mechanisms of action in methicillin-resistant S. aureus (MRSA), including a previously unidentified mechanism.…”

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confidence: 99%

“…Telavancin and other lipoglycopeptides exhibit superior in vitro activity compared to vancomycin (28,30,31,37,39,48), including rapid, concentration-dependent bactericidal activity against glycopeptide-susceptible organisms as well as glycopeptide-intermediate susceptible Staphylococcus aureus and vancomycin-resistant S. aureus (5,15,43; K. D. Leuthner, C. M. Cheung, and M. J. Rybak, Abstr. 44th Intersci.…”

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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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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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“…The rapid spread of resistance to these two drugs through pathogenic bacterial populations is an acute public health concern, and the discovery of additional natural or semisynthetic glycopeptides with more effective antibiotic activities has been targeted (1). A broad spectrum of vancomycin and teicoplanin derivatives has been generated through chemoenzymatic synthesis, and their activity toward pathogenic enterococcal strains was determined (2)(3)(4)(5)(6)(7)(8)(9). Interestingly, derivatives containing a hydrophobic substituent were generally found to be significantly more active against both glycopeptide-sensitive and glycopeptide-resistant strains.…”

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confidence: 99%

The Activity of Glycopeptide Antibiotics against Resistant Bacteria Correlates with Their Ability To Induce the Resistance System

Kwun

Hong

2014

Antimicrob Agents Chemother

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Glycopeptide antibiotics containing a hydrophobic substituent display the best activity against vancomycin-resistant enterococci, and they have been assumed to be poor inducers of the resistance system. Using a panel of 26 glycopeptide derivatives and the model resistance system in Streptomyces coelicolor, we confirmed this hypothesis at the level of transcription. Identification of the structural glycopeptide features associated with inducing the expression of resistance genes has important implications in the search for more effective antibiotic structures.

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The Role of Hydrophobic Substituents in the Biological Activityof Glycopeptide Antibiotics

Cited by 105 publications

References 10 publications

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

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

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

The Activity of Glycopeptide Antibiotics against Resistant Bacteria Correlates with Their Ability To Induce the Resistance System

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