Bacterial resistance to vancomycin: five genes and one missing hydrogen bond tell the story

Walsh, Christopher T.; Fisher, Stewart L.; Park, I.-S.; Prahalad, Murali K.; Wu, Zezhou

doi:10.1016/s1074-5521(96)90079-4

Cited by 385 publications

(269 citation statements)

References 31 publications

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“…[11,[21][22][23][24] This alteration amountst ot he replacement of an amide bond by an ester linkage,t hereby eliminating one of the key hydrogen bonds, and greatly decreasing the binding affinity of 1 to DADLacr elative to DADA. [25][26][27] Several promising approaches have been developedt o counter the risk of widespread infection, [28] with much emphasis devoted towards the development of vancomycina nalogues;o ften through chemical modification.…”

mentioning

confidence: 99%

Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]‐Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE

Silverman

Moses

Sharpless

2016

Chemistry A European J

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Vancomycin has long been considered adrug of last resort. Its efficiencyi nt reating multiple drug-resistant bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA), hash ad ap rofounde ffect on the treatment of life-threatening infections. However,t he emergence of resistance to vancomycin is ac ause for significantw orldwide concern, promptingt he urgentd evelopmento fn ew effective treatments for antibiotic resistant bacterial infections. Harnessingthe benefits of multivalency and cooperativitya gainst vancomycin-resistant strains, we report aC lick Chemistry approach towards reengineered vancomycin derivatives and the synthesis of an umber of dimers with increased potency against MRSA and vancomycin resistant Enterococci (VRE;V anB). These semi-synthetic dimericl igandsw ere linked together with great efficiencyu sing the powerful CuAACr eaction, demonstrating high levels of selectivity and purity.

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confidence: 99%

Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]‐Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE

Silverman

Moses

Sharpless

2016

Chemistry A European J

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“…For this reason, it was originally suggested that pathogens might never acquire resistance to vancomycin because it would require them to remodel the peptidoglycan biosynthetic pathway itself. In the late 1980s, however, the first clinical isolates of VRE appeared and were found to reprogram cell wall biosynthesis such that the pendant pentapeptide of peptidoglycan precursors terminated in D-alanyl-D-lactate (D-Ala-D-Lac), rather than in D-Ala-D-Ala (7)(8)(9)(10)(11)(12). The affinity of vancomycin for precursors terminating in D-Ala-D-Lac is ϳ1000-fold lower than for precursors terminating D-Ala-D-Ala We have shown previously that the non-pathogen Streptomyces coelicolor carries a gene cluster conferring inducible, high-level resistance to vancomycin (13).…”

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The Role of the Novel Fem Protein VanK in Vancomycin Resistance in Streptomyces coelicolor

Hong

Hutchings

Hill

et al. 2005

Journal of Biological Chemistry

141

139

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The spread of vancomycin resistance among pathogenic bacteria is an important public health concern. Ever since vancomycin-resistant strains of pathogenic Enterococcus faecalis and Enterococcus faecium (VRE) first emerged in the late 1980s, the intergeneric transfer of vancomycin resistance from these strains to methicillin-resistant Staphylococcus aureus, a major killer in hospital-acquired infections, has been widely anticipated. This recently became a reality with the first reports of clinical isolates of vancomycin-resistant Staphylococcus aureus (VRSA) 1 from hospitals in the United States (1-4). Vancomycin and other glycopeptide antibiotics inhibit cell wall biosynthesis in Gram-positive bacteria but not in Gramnegative bacteria because they cannot penetrate the outer membrane permeability barrier. They bind the D-alanyl-D-alanine (D-Ala-D-Ala) terminus of lipid-attached peptidoglycan precursors on the outside of the cytoplasmic membrane (5, 6), and this interaction blocks the formation of mature peptidoglycan, principally by denying transpeptidase access to its substrate, thus preventing formation of the peptide cross-links between polysaccharide strands that give the cell wall its structural rigidity. Because of the distinctive mode of action of vancomycin, mutations in transpeptidase cannot give rise to drug resistance. For this reason, it was originally suggested that pathogens might never acquire resistance to vancomycin because it would require them to remodel the peptidoglycan biosynthetic pathway itself. In the late 1980s, however, the first clinical isolates of VRE appeared and were found to repro- We have shown previously that the non-pathogen Streptomyces coelicolor carries a gene cluster conferring inducible, high-level resistance to vancomycin (13). S. coelicolor is the model species of a genus of Gram-positive, mycelial soil bacteria responsible for the production of two-thirds of the commercially important antibiotics. S. coelicolor itself does not make a glycopeptide, but all of the known glycopeptide antibiotics are produced by actinomycetes, the family to which the streptomycetes belong. Because most non-pathogenic actinomycetes live in the soil, it seems likely that S. coelicolor encounters glycopeptide producers and that the van gene cluster therefore confers a selective advantage. Further, it is widely believed that all glycopeptide resistance genes are ultimately derived from actinomycete glycopeptide producers (14), which must carry these genes to avoid autotoxicity. Consistent with this idea, the S. coelicolor resistance genes are clearly associated with a laterally acquired DNA element. 2The S. coelicolor cluster consists of seven genes, vanSR-JKHAX ( Fig. 1) (13). vanHAX are orthologous to the genes found in VRE strains. vanR and vanS encode a two-component signal transduction system that mediates transcriptional in-* This work was funded by Biotechnology and Biological Sciences Research Council Grant 208/P20040 (to H-J. H. and M. J. B.) and by a grant-in-aid to the John Innes C...

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“…The emergence of vancomycin resistance in the last decade has caused considerable concern because this drug is widely used to treat methicillin-resistant Gram-positive infections and there are few alternatives to it. The most common forms of resistance to vancomycin occur in enterococcal strains and involve the acquisition of a set of genes encoding proteins that direct peptidoglycan precursors to incorporate D-Ala-D-Lac (Lac ϭ lactate) instead of D-Ala-D-Ala (3,4). Because vancomycin does not bind D-Ala-D-Lac (Fig.…”

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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.

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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Bacterial resistance to vancomycin: five genes and one missing hydrogen bond tell the story

Cited by 385 publications

References 31 publications

Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]‐Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE

Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]‐Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE

The Role of the Novel Fem Protein VanK in Vancomycin Resistance in Streptomyces coelicolor

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

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