Chemical phylogenetics of the staphylococcal quorum sensing landscape

Staphylococci utilize secreted autoinducing peptides (AIPs) to regulate group behaviour through a process called quorum sensing (QS). Here, we survey the QS interaction landscape within the Staphylococcus genus by assembling a unique compound collection, comprising all the currently known AIPs. These ribosomally synthesized and posttranslationally modified peptides (RiPPs) were obtained by chemical synthesis and mapping of their ability to modulate QS was evaluated using reporter strains of common human and animal colonizing pathogens ( S. aureus, S. epidermidis, S. lugdunensis ). The resulting map of >200 native QS interactions provides a holistic view of nodes that contribute to the complex signalling network within the Staphylococcus genus. This overview reveals surprising cross-species QS induction and identify the first pan-inhibitory AIP, which is then shown to attenuate MRSA induced skin infection in a mouse model. Our results expose a complex universe of possible staphylococcal interactions and provide further impetus for development of therapeutics based on QS modulators targeting antibiotic resistant pathogens. ### Competing Interest Statement The University of Copenhagen has filed a PCT application (Cysteine derivatives as bacterial antivirulence agents - EP2020/060066) with B.H.G and C.A.O. listed as co-inventors.