Limits...
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.

Show MeSH

Related in: MedlinePlus

Structures of solonamideA and solonamide B, which were isolatedfrom a marine Photobacterium and display agr inhibitory activity. Given the structural similaritiesof these analogues to the tr-AIP-2 scaffold, it is postulated thatthey may serve as competitive inhibitors of the AgrC receptor.61
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585718&req=5

fig5: Structures of solonamideA and solonamide B, which were isolatedfrom a marine Photobacterium and display agr inhibitory activity. Given the structural similaritiesof these analogues to the tr-AIP-2 scaffold, it is postulated thatthey may serve as competitive inhibitors of the AgrC receptor.61

Mentions: Thus, present endeavors to develop a global AgrCcompetitive inhibitorhave focused on developing analogues based on the native S.aureus AIP structures. However, it appears that macrocyclicpeptides from other bacteria may provide valuable leads. For instance,solonamide A and solonamide B (Figure 5, compounds 21 and 22, respectively), which were isolatedfrom a marine Photobacterium, display agr inhibitory activity.61 It was speculatedthat the solonamides may serve as quorum sensing signals for Photobacterium, and the obvious structural similaritiesof with tr-AIP-2 and tr-AIP-3 suggest they may function as competitiveinhibitors of the S. aureus AgrC receptor.61 As previously outlined, structural investigationsof the tr-AIP-2 scaffold demonstrated that adjacent leucine and phenylalanineresidues are crucial for potent AgrC competitive inhibition whilesubstitution of the thiolactone moiety with a lactone has minimalimpact on inhibitory activity;47,53,56 each of these features is present within the solonamide scaffold.Although IC50 values were not reported, Northern blot analysisconfirmed the agr interfering activity of the solonamidesin both S. aureus strain 8325-4 and the highly virulentCA-MRSA strain USA300.61


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

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

Structures of solonamideA and solonamide B, which were isolatedfrom a marine Photobacterium and display agr inhibitory activity. Given the structural similaritiesof these analogues to the tr-AIP-2 scaffold, it is postulated thatthey may serve as competitive inhibitors of the AgrC receptor.61
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Structures of solonamideA and solonamide B, which were isolatedfrom a marine Photobacterium and display agr inhibitory activity. Given the structural similaritiesof these analogues to the tr-AIP-2 scaffold, it is postulated thatthey may serve as competitive inhibitors of the AgrC receptor.61
Mentions: Thus, present endeavors to develop a global AgrCcompetitive inhibitorhave focused on developing analogues based on the native S.aureus AIP structures. However, it appears that macrocyclicpeptides from other bacteria may provide valuable leads. For instance,solonamide A and solonamide B (Figure 5, compounds 21 and 22, respectively), which were isolatedfrom a marine Photobacterium, display agr inhibitory activity.61 It was speculatedthat the solonamides may serve as quorum sensing signals for Photobacterium, and the obvious structural similaritiesof with tr-AIP-2 and tr-AIP-3 suggest they may function as competitiveinhibitors of the S. aureus AgrC receptor.61 As previously outlined, structural investigationsof the tr-AIP-2 scaffold demonstrated that adjacent leucine and phenylalanineresidues are crucial for potent AgrC competitive inhibition whilesubstitution of the thiolactone moiety with a lactone has minimalimpact on inhibitory activity;47,53,56 each of these features is present within the solonamide scaffold.Although IC50 values were not reported, Northern blot analysisconfirmed the agr interfering activity of the solonamidesin both S. aureus strain 8325-4 and the highly virulentCA-MRSA strain USA300.61

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