Metabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound

Influenza Virus (IV) infections cause severe respiratory illnesses that can be complicated by Bacterial super-infections. Previously, we identified the cellular Raf-MEK-ERK cascade as a promising Antiviral target. Inhibitors of MEK, such as CI-1040, showed potent Antiviral activity. However, it remained unclear if this inhibitor and its active form, ATR-002, might sensitize host cells to either IV or secondary Bacterial infections. To address these questions, we studied the anti-pathogen activity of ATR-002 in comparison to CI-1040, particularly, its impact on Staphylococcus aureus (S. aureus), which is a major cause of IV super-infections. We analysed IV and S. aureus titres in vitro during super-infection in the presence and absence of the drugs and characterized the direct impact of ATR-002 on Bacterial growth and phenotypic changes. Importantly, neither CI-1040 nor ATR-002 treatment led to increased Bacterial titres during super-infection, indicating that the drug does not sensitize cells for Bacterial infection. In contrast, we rather observed reduced Bacterial titres in presence of ATR-002. Surprisingly, ATR-002 also led to reduced Bacterial growth in suspension cultures, reduced stress- and Antibiotic tolerance without resistance induction. Our data identified for the first time that a particular MEK-inhibitor metabolite exhibits direct Antibacterial activity, which is likely due to interference with the Bacterial PknB kinase/Stp Phosphatase signalling system.