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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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Schematic diagram of the transglycoylase active site showing doner and acceptor sites. Residue numbers in the acceptor sites refer to those determined for S. aureus monofunctional transglycosylase in relation to lipid II analogue as described by Huang et al. [28].
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f0005: Schematic diagram of the transglycoylase active site showing doner and acceptor sites. Residue numbers in the acceptor sites refer to those determined for S. aureus monofunctional transglycosylase in relation to lipid II analogue as described by Huang et al. [28].

Mentions: In the search for new treatments of bacterial infections and to combat the increasing threat of resistance to existing antimicrobials, there is renewed interest in the exploitation of existing validated targets with novel approaches. With respect to bacterial cell wall biosynthesis, the validity of the peptidoglycan biosynthetic apparatus is well established, particularly in consideration of the fact that many of these antimicrobial targets exist at or beyond the extra-cytoplasmic surface of the cell membrane and are well conserved across all bacterial species [1,2]. The biosynthetic pathway leading to peptidoglycan precursor lipid II and the generalised scheme for its polymerisation into the peptidoglycan layer is well documented. Briefly, uridine 5′-pyrophosphoryl-N-acetyl muramyl-l-alanyl-γ-d-glutamyl-meso-diaminopimelyl-d-alanyl-d-alanine (UDP-MurNAc-L-Ala-D-Glu-L-(Lys/meso-DAP)-D-Ala-D-Ala) or its l-lysine derivative (UDP-MurNAc-L-Ala-D-Glu-L-(Lys)-D-Ala-D-Ala) is produced in the cytoplasmic pathway before linkage at the cytoplasmic membrane surface to an undecaprenyl (C55) carrier lipid, prior to the addition of GlcNAc, forming lipid II [3]. This peptidoglycan precursor is then transferred to the outer surface of the cytoplasmic membrane where it is polymerised by monofunctional transglycosylases and class A bifunctional Penicillin Binding Proteins (PBPs) into long glycan chains [4] (Fig. 1). The transpeptidase activity of Class A and B PBPs then produce inter-strand peptide cross-links from pentapeptides emanating from adjacent glycan chains. The resulting polymer has the mechanical strength and rigidity required to resist cytoplasmic osmotic stress and forms a scaffold for a number of extracellular structures and functions.


Prospects for novel inhibitors of peptidoglycan transglycosylases.

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

Schematic diagram of the transglycoylase active site showing doner and acceptor sites. Residue numbers in the acceptor sites refer to those determined for S. aureus monofunctional transglycosylase in relation to lipid II analogue as described by Huang et al. [28].
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

f0005: Schematic diagram of the transglycoylase active site showing doner and acceptor sites. Residue numbers in the acceptor sites refer to those determined for S. aureus monofunctional transglycosylase in relation to lipid II analogue as described by Huang et al. [28].
Mentions: In the search for new treatments of bacterial infections and to combat the increasing threat of resistance to existing antimicrobials, there is renewed interest in the exploitation of existing validated targets with novel approaches. With respect to bacterial cell wall biosynthesis, the validity of the peptidoglycan biosynthetic apparatus is well established, particularly in consideration of the fact that many of these antimicrobial targets exist at or beyond the extra-cytoplasmic surface of the cell membrane and are well conserved across all bacterial species [1,2]. The biosynthetic pathway leading to peptidoglycan precursor lipid II and the generalised scheme for its polymerisation into the peptidoglycan layer is well documented. Briefly, uridine 5′-pyrophosphoryl-N-acetyl muramyl-l-alanyl-γ-d-glutamyl-meso-diaminopimelyl-d-alanyl-d-alanine (UDP-MurNAc-L-Ala-D-Glu-L-(Lys/meso-DAP)-D-Ala-D-Ala) or its l-lysine derivative (UDP-MurNAc-L-Ala-D-Glu-L-(Lys)-D-Ala-D-Ala) is produced in the cytoplasmic pathway before linkage at the cytoplasmic membrane surface to an undecaprenyl (C55) carrier lipid, prior to the addition of GlcNAc, forming lipid II [3]. This peptidoglycan precursor is then transferred to the outer surface of the cytoplasmic membrane where it is polymerised by monofunctional transglycosylases and class A bifunctional Penicillin Binding Proteins (PBPs) into long glycan chains [4] (Fig. 1). The transpeptidase activity of Class A and B PBPs then produce inter-strand peptide cross-links from pentapeptides emanating from adjacent glycan chains. The resulting polymer has the mechanical strength and rigidity required to resist cytoplasmic osmotic stress and forms a scaffold for a number of extracellular structures and functions.

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