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Given its high resistance, enhanced virulence, and high transmissibility, community-associated methicillin-resistant  Staphylococcus aureus  (CA-MRSA) pneumonia is highly associated with high morbidity and mortality. Anti-virulence therapy is a promising strategy that bypasses the evolutionary pressure on the bacterium to develop resistance. RNAIII-inhibiting peptide (RIP), as an accessory gene regulator ( agr )-specific inhibitor, significantly restricts the virulence of  S. aureus  and protects infected mice from death by blocking the  agr  quorum sensing system. The protective effects of RIP on the neutropenic mice completely disappeared in a neutrophil-deleted mouse infection model, but not in the macrophage-deleted mice. This result confirmed that the in vivo antibacterial activity of RIP is highly associated with neutrophil function. Phenol-soluble modulins (PSMs), as major leukocyte lysis toxins of CA-MRSA, are directly regulated by the  agr  system. In this experiment, PSMα1, 2, and 3 significantly induced neutrophil necroptosis by activating mixed lineage kinase-like protein (MLKL) phosphorylation and increasing lactate dehydrogenase release. The  S. aureus  supernatants harvested from the  agr  or  psmα  mutant strains both decreased the phosphorylation level of MLKL and cell lysis. PSMα1-mediated neutrophil lysis was significantly inhibited by necrosulfonamide, necrostatin-1, TNFα antibody, and WRW4. These results showed PSMα1 induced necroptosis depends on formylpeptide receptor 2 (FPR2)-mediated autocrine TNFα. Moreover, the neutrophil necroptosis induced by  S. aureus  was significantly suppressed and pneumonia was effectively prevented by the blockage of  agrA  and  psmα  expression levels. These findings indicate that PSMα-induced necroptosis is a major cause of lung pathology in  S. aureus  pneumonia and suggest that interfering with the  agr  quorum sensing signaling pathway is a potential therapeutic strategy.

Inhibiting PSMα-induced neutrophil necroptosis protects mice with MRSA pneumonia by blocking the agr system