Mapping of Quorum Sensing Landscape of Commensal and Pathogenic Staphylococci Reveals a Largely Inhibitory Interaction Network
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Staphylococci utilize secreted autoinducing peptides (AIPs) to regulate group behaviour through a process called quorum sensing (QS). For staphylococcal pathogens such as S. aureus , QS regulates expression of major virulence factors and QS inhibition has been proposed as an alternative to antibiotics for treatment of infections with methicillin resistant S. aureus (MRSA). Here, we surveyed the interaction map between QS systems of the pathogens Staphylococcus aureus, Staphylococcus epidermidis , and Staphylococcus lugdunensis and the 36 currently known AIPs from 22 staphylococcal species. We identified seven of these ribosomally synthesized and post-translationally modified peptides (RiPPs) in this study and all synthetic peptides were assessed for their ability to modulate QS. The mapped interactions of >280 native QS pairings were divided into human- and animal-associated staphylococci showing substantial differences in inhibitory potencies between the groups. In particular, AIPs of the bovine-associated species S. simulans displayed potential as QS inhibitors in the strains investigated in this study and were therefore chosen as starting point for a structure–activity relationship study. This study provides insights into the requirements for QS interference, yielding the most potent inhibitors reported to date for S. epidermidis and S. lugdunensis . Further, we tested an S. simulans AIP as anti-virulence agent in an assay to assess risk of acquired suppression of the inhibitory effect, and we established an assay set-up to successfully monitor agr deactivation of virulent MRSA by the QS inhibitor. Finally, a peptide was shown to attenuate skin infection caused by MRSA in a mouse model. Our results reveal a complex network of staphylococcal interactions and provide further impetus for the development of therapeutic strategies, based on QS modulation to target antibiotic-resistant pathogens.
