title: The agr Inhibitors Solonamide B and Analogues Alter Immune Responses to Staphylococccus aureus but Do Not Exhibit Adverse Effects on Immune Cell Functions.
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.
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Mara
authors.initials: M
authors.lastname: Baldry
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Betül
authors.initials: B
authors.lastname: Kitir
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Frøkiær
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Simon B
authors.initials: SB
authors.lastname: Christensen
authors.affiliation: Host Microbes Interactomics Group, Wageningen University, Wageningen, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Taverne
authors.affiliation: Host Microbes Interactomics Group, Wageningen University, Wageningen, The Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Meijerink
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Olsen
authors.affiliation: Host Microbes Interactomics Group, Wageningen University, Wageningen, The Netherlands.
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Wells
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Ingmer
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006460:Hemolysin Proteins / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics
chemical_list: C095698:Agr protein, Staphylococcus aureus; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D016207:Cytokines; D005353:Fibronectins; D006460:Hemolysin Proteins; D010456:Peptides, Cyclic; D015534:Trans-Activators; C558621:solomonamide B; C021091:staphylococcal alpha-toxin