Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms
| Autor: | Stephan A. Sieber, Manfred Rohde, Mathias W. Hackl, Eva Medina, Vadim S. Korotkov, Elena Kunold, Franziska A. Mandl, William M. Wuest, Christian Fetzer, Robert Macsics, Philipp Le, Maria Reinecke, Bernhard Kuster, Johannes Lehmann, Diego Chaves-Moreno, Katharina Rox, Stephan M. Hacker, Dietmar H. Pieper, Iris Antes, Megan C. Jennings, Ilke Ugur |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Methicillin-Resistant Staphylococcus aureus medicine.drug_class General Chemical Engineering Antibiotics Drug resistance Microbial Sensitivity Tests Molecular Dynamics Simulation 010402 general chemistry medicine.disease_cause 01 natural sciences Article Microbiology Structure-Activity Relationship In vivo Cell Line Tumor medicine Animals Humans Benzodioxoles Protein Kinase Inhibitors biology Molecular Structure 010405 organic chemistry Chemistry Biofilm Drug Repositioning General Chemistry Sorafenib biology.organism_classification 0104 chemical sciences Anti-Bacterial Agents Mice Inbred C57BL Drug repositioning Staphylococcus aureus Biofilms Female Antibacterial activity Autolysis Bacteria |
| Zdroj: | Nature chemistry International United States England |
| ISSN: | 1755-4349 1755-4330 |
| Popis: | New drugs are desperately needed to combat methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we report screening commercial kinase inhibitors for antibacterial activity and found the anticancer drug sorafenib as major hit that effectively kills MRSA strains. Varying the key structural features led to the identification of a potent analogue, PK150, that showed antibacterial activity against several pathogenic strains at submicromolar concentrations. Furthermore, this antibiotic eliminated challenging persisters as well as established biofilms. PK150 holds promising therapeutic potential as it did not induce in vitro resistance, and shows oral bioavailability and in vivo efficacy. Analysis of the mode of action using chemical proteomics revealed several targets, which included interference with menaquinone biosynthesis by inhibiting demethylmenaquinone methyltransferase and the stimulation of protein secretion by altering the activity of signal peptidase IB. Reduced endogenous menaquinone levels along with enhanced levels of extracellular proteins of PK150-treated bacteria support this target hypothesis. The associated antibiotic effects, especially the lack of resistance development, probably stem from the compound's polypharmacology. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink