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.

• Authors: Christin Bruchhagen, Marcel Jarick, Carolin Mewis, Tobias Hertlein, Silke Niemann, Knut Ohlsen, Georg Peters, Oliver Planz, Stephan Ludwig, Christina Ehrhardt
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 9114 (06 14 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29904167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Anti-Bacterial Agents
• Benzamides
• Protein Kinase Inhibitors
• MAP Kinase Kinase Kinases

Topics

• A549 Cells
• Animals
• Anti-Bacterial Agents (pharmacokinetics, pharmacology)
• Benzamides (pharmacokinetics, pharmacology)
• Dogs
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Madin Darby Canine Kidney Cells
• Protein Kinase Inhibitors (pharmacokinetics, pharmacology)
• Staphylococcal Infections (drug therapy, metabolism, pathology)
• Staphylococcus aureus (growth & development)