The agr Inhibitors Solonamide B and Analogues Alter Immune Responses to Staphylococccus aureus but Do Not Exhibit Adverse Effects on Immune Cell Functions

PLoS One. 2016 Jan 5;11(1):e0145618. doi: 10.1371/journal.pone.0145618. eCollection 2016.

Abstract

Staphylococcus aureus infections are becoming increasingly difficult to treat due to antibiotic resistance with the community-associated methicillin-resistant S. aureus (CA-MRSA) strains such as USA300 being of particular concern. The inhibition of bacterial virulence has been proposed as an alternative approach to treat multi-drug resistant pathogens. One interesting anti-virulence target is the agr quorum-sensing system, which regulates virulence of CA-MRSA in response to agr-encoded autoinducing peptides. Agr regulation confines exotoxin production to the stationary growth phase with concomitant repression of surface-expressed adhesins. Solonamide B, a non-ribosomal depsipeptide of marine bacterial origin, was recently identified as a putative anti-virulence compound that markedly reduced expression of α-hemolysin and phenol-soluble modulins. To further strengthen solonamide anti-virulence candidacy, we report the chemical synthesis of solonamide analogues, investigation of structure-function relationships, and assessment of their potential to modulate immune cell functions. We found that structural differences between solonamide analogues confer significant differences in interference with agr, while immune cell activity and integrity is generally not affected. Furthermore, treatment of S. aureus with selected solonamides was found to only marginally influence the interaction with fibronectin and biofilm formation, thus addressing the concern that application of compounds inducing an agr-negative state may have adverse interactions with host factors in favor of host colonization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Adhesion / drug effects
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Bacterial Toxins / metabolism
  • Biofilms / drug effects
  • Biofilms / growth & development
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / immunology
  • Cells, Cultured
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibronectins / metabolism
  • Hemolysin Proteins / metabolism
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Mice, Inbred C57BL
  • Molecular Structure
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Staphylococcal Infections / immunology
  • Staphylococcal Infections / microbiology
  • Staphylococcal Infections / prevention & control*
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / pathogenicity
  • Staphylococcus aureus / physiology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Virulence / genetics

Substances

  • Agr protein, Staphylococcus aureus
  • Bacterial Proteins
  • Bacterial Toxins
  • Cytokines
  • Fibronectins
  • Hemolysin Proteins
  • Peptides, Cyclic
  • Trans-Activators
  • solomonamide B
  • staphylococcal alpha-toxin

Grant support

This work was supported by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement N° 289285, the Lundbeck Foundation’s Group Leader Fellowship (C.A.O.) and the Carlsberg Foundation (C.A.O.).