Metabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound
| Autor: | Tobias Hertlein, Carolin Mewis, Marcel Jarick, Silke Niemann, Oliver Planz, Knut Ohlsen, Christina Ehrhardt, Christin Bruchhagen, Georg Peters, Stephan Ludwig |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Staphylococcus aureus Multidrug tolerance Metabolite lcsh:Medicine Bacterial growth medicine.disease_cause Article Virus Madin Darby Canine Kidney Cells Microbiology 03 medical and health sciences chemistry.chemical_compound Dogs medicine Animals Humans lcsh:Science Protein Kinase Inhibitors A549 cell Multidisciplinary Kinase MEK inhibitor lcsh:R Staphylococcal Infections MAP Kinase Kinase Kinases Anti-Bacterial Agents 030104 developmental biology chemistry A549 Cells Benzamides lcsh:Q |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-27445-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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