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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

Structures and IC50 values of the small molecule agr inhibitorssavirin (24), the gout drugbenzbromarone (25), and C094-0010 (26) thatwere identified from a number of high-throughput screening program.74−76
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fig8: Structures and IC50 values of the small molecule agr inhibitorssavirin (24), the gout drugbenzbromarone (25), and C094-0010 (26) thatwere identified from a number of high-throughput screening program.74−76

Mentions: Several synthetic and natural product small molecule analogueswith agr inhibitory properties including savirin(Staphylococcus aureusvirulence inhibitor) (compound 24, Figure 8), benzbromarone (compound 25, Figure 8), and a benzo-1,4-dioxane analogue (compound 26, Figure 8) have been described. These compoundswere identified from extensive random screening programs, and eachinhibits AIP-induced production of RNAIII transcripts and thus virulencefactors such as α-hemolysin and lipase.74−76


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

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

Structures and IC50 values of the small molecule agr inhibitorssavirin (24), the gout drugbenzbromarone (25), and C094-0010 (26) thatwere identified from a number of high-throughput screening program.74−76
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Structures and IC50 values of the small molecule agr inhibitorssavirin (24), the gout drugbenzbromarone (25), and C094-0010 (26) thatwere identified from a number of high-throughput screening program.74−76
Mentions: Several synthetic and natural product small molecule analogueswith agr inhibitory properties including savirin(Staphylococcus aureusvirulence inhibitor) (compound 24, Figure 8), benzbromarone (compound 25, Figure 8), and a benzo-1,4-dioxane analogue (compound 26, Figure 8) have been described. These compoundswere identified from extensive random screening programs, and eachinhibits AIP-induced production of RNAIII transcripts and thus virulencefactors such as α-hemolysin and lipase.74−76

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