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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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Related in: MedlinePlus

Schematic of the main techniques currently available to assay transglycosylase activity allowing inhibitor discovery as discussed in Section 2. A cartoon representation of a typical reaction trace is shown for each technique and section numbers corresponding to the text are included.
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f0010: Schematic of the main techniques currently available to assay transglycosylase activity allowing inhibitor discovery as discussed in Section 2. A cartoon representation of a typical reaction trace is shown for each technique and section numbers corresponding to the text are included.

Mentions: Bacterial transglycosylases have been studied for over 50 years [10]. The discovery and development of novel transglycosylase inhibitors has been highly dependent on appropriate activity assays. However, progress has been hampered by the lack of quantitative and high throughput approaches capable of fast, accurate enzyme activity measurement. In addition, such efforts have been affected by the relative chemical complexity and lack of availability of the transglycosylase substrate, lipid II. Chemical and chemi-enzymatic approaches to overcome this hurdle have been reported by several groups, [11–22]. In addition, lipid II and other peptidoglycan intermediates have become available from the UK Bacterial Cell Wall Biosynthesis Network (UK-BaCWAN). Since both the transglycosylase enzymes and substrate are within a lipid membrane environment, assay conditions and design needs to factor in these chemical properties and physical limitations. The solution of several X-ray crystal structures of mono-functional and bifunctional enzymes has enhanced structure based drug design efforts [7,23–28], an advance which has depended upon the design and implementation of reliable and accurate high-throughput assays. The following sections discuss the main assay types currently available, whilst Fig. 2 and Table 1 provide concise summaries.


Prospects for novel inhibitors of peptidoglycan transglycosylases.

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

Schematic of the main techniques currently available to assay transglycosylase activity allowing inhibitor discovery as discussed in Section 2. A cartoon representation of a typical reaction trace is shown for each technique and section numbers corresponding to the text are included.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

f0010: Schematic of the main techniques currently available to assay transglycosylase activity allowing inhibitor discovery as discussed in Section 2. A cartoon representation of a typical reaction trace is shown for each technique and section numbers corresponding to the text are included.
Mentions: Bacterial transglycosylases have been studied for over 50 years [10]. The discovery and development of novel transglycosylase inhibitors has been highly dependent on appropriate activity assays. However, progress has been hampered by the lack of quantitative and high throughput approaches capable of fast, accurate enzyme activity measurement. In addition, such efforts have been affected by the relative chemical complexity and lack of availability of the transglycosylase substrate, lipid II. Chemical and chemi-enzymatic approaches to overcome this hurdle have been reported by several groups, [11–22]. In addition, lipid II and other peptidoglycan intermediates have become available from the UK Bacterial Cell Wall Biosynthesis Network (UK-BaCWAN). Since both the transglycosylase enzymes and substrate are within a lipid membrane environment, assay conditions and design needs to factor in these chemical properties and physical limitations. The solution of several X-ray crystal structures of mono-functional and bifunctional enzymes has enhanced structure based drug design efforts [7,23–28], an advance which has depended upon the design and implementation of reliable and accurate high-throughput assays. The following sections discuss the main assay types currently available, whilst Fig. 2 and Table 1 provide concise summaries.

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