Rosmarinic acid prevents refractory bacterial pneumonia through regulating Keap1/Nrf2-mediated autophagic pathway and mitochondrial oxidative stress

Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of bacterial pneumonia, featured with exuberant inflammatory cytokine production, extensive oxidative stress and tissue injury. The Keap1/Nrf2 system is the major apparatus essential for host defense against oxidative and electrophilic stresses of both exogenous and endogenous origins, representing a logical target for host-directed strategy to treat severe inflammatory diseases including MRSA-induced pneumonia. In an effort to search therapeutics for bacterial pneumonia, we identify rosmarinic acid (RA) as a covalent modifier of Keap1 and hence an activator of Nrf2. Specifically, RA forms a covalent bond with the cysteine 151 of Keap1 in BTB domain, and blocks its association with Nrf2 for proteasome-mediated degradation. Consequently, RA treatment caused the increased Nrf2 nuclear translocation to initiate antioxidant and mitochondrial biogenic programs, as well as macrophage bactericidal activity through inducing autophagic pathway, which eventually led to expedited bacterial eradication, inflammation resolution, and disease recovery. Collectively, our findings establish RA as a specific inducer of Nrf2 and show its potential to prevent MRSA pneumonia.