Nielsen, Anita4; Månsson, Maria1; Bojer, Martin S.4; Gram, Lone1; Larsen, Thomas Ostenfeld1; Novick, Richard P.5; Frees, Dorte4; Frøkiær, Hanne4; Ingmer, Hanne4
1 Department of Systems Biology, Technical University of Denmark2 Natural Product Chemistry, Department of Systems Biology, Technical University of Denmark3 Bacterial Ecophysiology and Biotechnology, Department of Systems Biology, Technical University of Denmark4 University of Copenhagen5 New York University School of Medicine
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and particularly the spread of community associated (CA)-MRSA strains such as USA300 is a concern, as these strains can cause severe infections in otherwise healthy adults. Recently, we reported that a cyclodepsipeptide termed Solonamide B isolated from the marine bacterium, Photobacterium halotolerans strongly reduces expression of RNAIII, the effector molecule of the agr quorum sensing system. Here we show that Solonamide B interferes with the binding of S. aureus autoinducing peptides (AIPs) to sensor histidine kinase, AgrC, of the agr two-component system. The hypervirulence of USA300 has been linked to increased expression of central virulence factors like a-hemolysin and the phenol soluble modulins (PSMs). Importantly, in strain USA300 Solonamide B dramatically reduced the activity of a-hemolysin and the transcription of psma encoding PSMs with an 80% reduction in toxicity of supernatants towards human neutrophils and rabbit erythrocytes. To our knowledge this is the first report of a compound produced naturally by a Gram-negative marine bacterium that interferes with agr and affects both RNAIII and AgrA controlled virulence gene expression in S. aureus.