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Attenuating Staphylococcus aureus virulence gene regulation: a medicinal chemistry perspective.

Gordon CP, Williams P, Chan WC - J. Med. Chem. (2013)

Bottom Line: There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models.These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA-DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators.We discuss the potential of specific examples of antivirulence agents for the management and treatment of staphylococcal infections.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.

ABSTRACT
Virulence gene expression in Staphylococcus aureus is tightly regulated by intricate networks of transcriptional regulators and two-component signal transduction systems. There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models. In this Perspective, we will provide insights into medicinal chemistry strategies for the development of chemical reagents that have the capacity to inhibit staphylococcal virulence expression. These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA-DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators. We discuss the potential of specific examples of antivirulence agents for the management and treatment of staphylococcal infections.

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Related in: MedlinePlus

Structure of tr-AcAIP-2 color-coded, thus indicating portionsofthe structure that are critical for inhibition of cognate (AgrC-2)and/or noncognate (AgrC-1) receptors.53
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fig3: Structure of tr-AcAIP-2 color-coded, thus indicating portionsofthe structure that are critical for inhibition of cognate (AgrC-2)and/or noncognate (AgrC-1) receptors.53

Mentions: Thus, in terms of AgrC-1 and AgrC-2inhibition, these SAR dataindicate that the cysteine and two C-terminal hydrophobic residuesat endocyclic positions 7 and 8 are crucial for inhibitory activitywhile the remainder of the molecule appears less important (Figure 3). In the case of noncognate agr inhibition, the serine residues at endocyclic positions 5 and 6can be replaced with an alkyl linker without dramatic loss of activity.53


Attenuating Staphylococcus aureus virulence gene regulation: a medicinal chemistry perspective.

Gordon CP, Williams P, Chan WC - J. Med. Chem. (2013)

Structure of tr-AcAIP-2 color-coded, thus indicating portionsofthe structure that are critical for inhibition of cognate (AgrC-2)and/or noncognate (AgrC-1) receptors.53
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585718&req=5

fig3: Structure of tr-AcAIP-2 color-coded, thus indicating portionsofthe structure that are critical for inhibition of cognate (AgrC-2)and/or noncognate (AgrC-1) receptors.53
Mentions: Thus, in terms of AgrC-1 and AgrC-2inhibition, these SAR dataindicate that the cysteine and two C-terminal hydrophobic residuesat endocyclic positions 7 and 8 are crucial for inhibitory activitywhile the remainder of the molecule appears less important (Figure 3). In the case of noncognate agr inhibition, the serine residues at endocyclic positions 5 and 6can be replaced with an alkyl linker without dramatic loss of activity.53

Bottom Line: There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models.These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA-DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators.We discuss the potential of specific examples of antivirulence agents for the management and treatment of staphylococcal infections.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.

ABSTRACT
Virulence gene expression in Staphylococcus aureus is tightly regulated by intricate networks of transcriptional regulators and two-component signal transduction systems. There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models. In this Perspective, we will provide insights into medicinal chemistry strategies for the development of chemical reagents that have the capacity to inhibit staphylococcal virulence expression. These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA-DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators. We discuss the potential of specific examples of antivirulence agents for the management and treatment of staphylococcal infections.

Show MeSH
Related in: MedlinePlus