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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

Structureof the Pseudomonas aeruginosa alkylquinolone,4-hydroxy-2-heptylquinoline-N-oxide, which displaysinhibitory effects against the agr system.
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fig10: Structureof the Pseudomonas aeruginosa alkylquinolone,4-hydroxy-2-heptylquinoline-N-oxide, which displaysinhibitory effects against the agr system.

Mentions: Some of the most intriguing natural compounds displaying agr inhibitory activities have emerged from investigationsof mixed microbial infections. A number of these studies have focusedon chronic infections within the airways of cystic fibrosis (CF) sufferersand led to the discovery that the prolonged growth of S. aureus with either Pseudomonas aeruginosa or with physiologicalconcentrations of the P. aeruginosa exoproduct 4-hydroxy-2-heptylquinoline N-oxide (HQNO, compound 39, Figure 10) selects for typical S. aureus small-colony variants (SCVs).79 However,SCVs are well-known for aminoglycoside resistance and persistencein chronic infections, including those found in CF.79 Evidence suggests that the development of SCVs is in partdue to HQNO-mediated repression of the agr system.In addition to other unknown mechanism(s) of action, HQNO apparentlyhas the capacity to inhibit agr group I with an IC50 of 1.3 μM (unpublished data from our lab).


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

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

Structureof the Pseudomonas aeruginosa alkylquinolone,4-hydroxy-2-heptylquinoline-N-oxide, which displaysinhibitory effects against the agr system.
© Copyright Policy
Related In: Results  -  Collection

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

fig10: Structureof the Pseudomonas aeruginosa alkylquinolone,4-hydroxy-2-heptylquinoline-N-oxide, which displaysinhibitory effects against the agr system.
Mentions: Some of the most intriguing natural compounds displaying agr inhibitory activities have emerged from investigationsof mixed microbial infections. A number of these studies have focusedon chronic infections within the airways of cystic fibrosis (CF) sufferersand led to the discovery that the prolonged growth of S. aureus with either Pseudomonas aeruginosa or with physiologicalconcentrations of the P. aeruginosa exoproduct 4-hydroxy-2-heptylquinoline N-oxide (HQNO, compound 39, Figure 10) selects for typical S. aureus small-colony variants (SCVs).79 However,SCVs are well-known for aminoglycoside resistance and persistencein chronic infections, including those found in CF.79 Evidence suggests that the development of SCVs is in partdue to HQNO-mediated repression of the agr system.In addition to other unknown mechanism(s) of action, HQNO apparentlyhas the capacity to inhibit agr group I with an IC50 of 1.3 μM (unpublished data from our lab).

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