Quorum-sensing control of sepsis in the coagulase-negative staphylococcal species Staphylococcus haemolyticus

Quorum sensing is often proposed as a target for antivirulence drug development against bacterial pathogens. Coagulase-negative staphylococci are leading causes of nosocomial blood infections and associated mortality. However, there is a severe lack of understanding how virulence and quorum sensing affect coagulase-negative staphylococcal sepsis. We show that the Agr quorum-sensing system has a strong impact on mortality from experimental sepsis caused by the exemplary coagulase-negative staphylococcal species Staphylococcus haemolyticus. This was based on strict Agr regulation of phenol-soluble modulin (PSM) toxins with PSM cytolytic capacity predominantly underlying the observed effect. These findings imply that Agr and PSMs represent promising targets for antivirulence drug development targeting sepsis caused by coagulase-negative staphylococci. This contrasts S. aureus blood infections, for which such approaches are considered less promising-a difference our results suggest is due to the PSM-focused mode of Agr control in coagulase-negative staphylococci.