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Prospects for novel inhibitors of peptidoglycan transglycosylases.

Galley NF, O'Reilly AM, Roper DI - Bioorg. Chem. (2014)

Bottom Line: The lack of novel antimicrobial drugs under development coupled with the increasing occurrence of resistance to existing antibiotics by community and hospital acquired infections is of grave concern.The targeting of biosynthesis of the peptidoglycan component of the bacterial cell wall has proven to be clinically valuable but relatively little therapeutic development has been directed towards the transglycosylase step of this process.Advances towards the isolation of new antimicrobials that target transglycosylase activity will rely on the development of the enzymological tools required to identify and characterise novel inhibitors of these enzymes.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.

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The structure of vancomycin and its derivative chlorobiphenyl vancomycin (CBP-V), which showed antibacterial activity against vancomycin-resistant Enterococci (VRE) [85] (discussed in Section 3.5).
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f0020: The structure of vancomycin and its derivative chlorobiphenyl vancomycin (CBP-V), which showed antibacterial activity against vancomycin-resistant Enterococci (VRE) [85] (discussed in Section 3.5).

Mentions: The natural product antibiotic vancomycin normally inhibits peptidoglycan polymerisation by binding to the terminal d-Ala-d-Ala moiety on the lipid II pentapeptide stem, inhibiting transpeptidation. Controversially, hydrophobic vancomycin derivatives have been shown to inhibit peptidoglycan polymerisation through preventing transglycosylation, most likely through binding the transglycosylase domain of PBPs and in the absence of dipeptide and depsi-peptide binding [34,82–84]. Common examples of vancomycin derivatives have lipid moieties at the aglycone or on the carbohydrates. One is produced from alkylating vancomycin on the vancosamine sugar with chlorobiphenyl, giving chlorobiphenyl-vancomycin (CBP-V) [85] (Fig. 4). CBP-V showed antibacterial activity against vancomycin-resistant strains, e.g. vancomycin-resistant Enterococci (VRE), where the di-peptide moiety in lipid II is substituted for d-Ala-d-lactate.


Prospects for novel inhibitors of peptidoglycan transglycosylases.

Galley NF, O'Reilly AM, Roper DI - Bioorg. Chem. (2014)

The structure of vancomycin and its derivative chlorobiphenyl vancomycin (CBP-V), which showed antibacterial activity against vancomycin-resistant Enterococci (VRE) [85] (discussed in Section 3.5).
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126109&req=5

f0020: The structure of vancomycin and its derivative chlorobiphenyl vancomycin (CBP-V), which showed antibacterial activity against vancomycin-resistant Enterococci (VRE) [85] (discussed in Section 3.5).
Mentions: The natural product antibiotic vancomycin normally inhibits peptidoglycan polymerisation by binding to the terminal d-Ala-d-Ala moiety on the lipid II pentapeptide stem, inhibiting transpeptidation. Controversially, hydrophobic vancomycin derivatives have been shown to inhibit peptidoglycan polymerisation through preventing transglycosylation, most likely through binding the transglycosylase domain of PBPs and in the absence of dipeptide and depsi-peptide binding [34,82–84]. Common examples of vancomycin derivatives have lipid moieties at the aglycone or on the carbohydrates. One is produced from alkylating vancomycin on the vancosamine sugar with chlorobiphenyl, giving chlorobiphenyl-vancomycin (CBP-V) [85] (Fig. 4). CBP-V showed antibacterial activity against vancomycin-resistant strains, e.g. vancomycin-resistant Enterococci (VRE), where the di-peptide moiety in lipid II is substituted for d-Ala-d-lactate.

Bottom Line: The lack of novel antimicrobial drugs under development coupled with the increasing occurrence of resistance to existing antibiotics by community and hospital acquired infections is of grave concern.The targeting of biosynthesis of the peptidoglycan component of the bacterial cell wall has proven to be clinically valuable but relatively little therapeutic development has been directed towards the transglycosylase step of this process.Advances towards the isolation of new antimicrobials that target transglycosylase activity will rely on the development of the enzymological tools required to identify and characterise novel inhibitors of these enzymes.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.

Show MeSH
Related in: MedlinePlus