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

Abstract

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.

MEK1 regulates pulmonary macrophage inflammatory responses and resolution of acute lung injury

“…MEK1/2-ERK1/2 pathway activation in alveolar macrophages from healthy human subjects and ARDS patients. The data from this murine model support a key role of the macrophage MEK1/2-ERK1/2 pathway in regulating the severity and resolution of inflammation following ALI, and is consistent with our previous findings and results from other groups demonstrating that application of pharmacological inhibitors of the MEK1/2-ERK1/2 pathway can reduce detrimental proinflammatory responses in murine models of lung injury (8,10), infection (9,22,23), asthma (24), sepsis (11,12), and malaria (25). Based on these findings and results from our current studies, we hypothesized that subjects with ARDS would have increased activation of the MEK1/2-ERK1/2 pathway in alveolar macrophages compared with healthy subjects without ARDS.…”

Viral and Bacterial Co-Infections in the Lungs: Dangerous Liaisons

“…Several in vitro superinfection models using monolayer cell lines or primary cells derived from epithelia or macrophages have been proposed-influenza/S. aureus in A549 cells [174,175], or RSV/S. pneumoniae in primary macrophages [128] provide important information on the host response and mutual virus/bacteria interactions.…”

“…Compared to the large number of clinical studies or in vivo experiments, there are relatively few experimental models of in vitro co-infections/superinfections described in the literature. Several in vitro superinfection models using monolayer cell lines or primary cells derived from epithelia or macrophages have been proposed—influenza/ S. aureus in A549 cells [ 174 , 175 ], or RSV/ S. pneumoniae in primary macrophages [ 128 ] provide important information on the host response and mutual virus/bacteria interactions. Although essential, these models present some limitations.…”

Direct Targeting of the Raf-MEK-ERK Signaling Cascade Inhibits Neuroblastoma Growth

“…Metabolic conversion of CI-1040 generates an anti-bacterial compound ATR-002, which interferes with the influenza life cycle by interrupting the Raf-MEK-ERK pathway in adenocarcinoma human alveolar basal epithelial cells [ 45 ]. We observed a dose-dependent induction of apoptosis and blockage of cell cycle progression at the S phase in NB cells by CI-1040 treatment.…”