2. Academic Validation
  3. Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

  • Nat Chem. 2020 Feb;12(2):145-158. doi: 10.1038/s41557-019-0378-7.
Philipp Le  # 1 2,  Elena Kunold  # 1 2 3,  Robert Macsics  # 1 2,  Katharina Rox 4 5,  Megan C Jennings 6,  Ilke Ugur 7,  Maria Reinecke 8 9 10,  Diego Chaves-Moreno 11,  Mathias W Hackl 1 2,  Christian Fetzer 1 2,  Franziska A M Mandl 1 2,  Johannes Lehmann 1 2,  Vadim S Korotkov 1 2,  Stephan M Hacker 12,  Bernhard Kuster 8 9 10 13,  Iris Antes 7,  Dietmar H Pieper 11,  Manfred Rohde 14,  William M Wuest 15 16,  Eva Medina 17,  Stephan A Sieber 18 19 20
Affiliations

Affiliations

  • 1 Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Garching bei München, Germany.
  • 2 Chair of Organic Chemistry II, Technische Universität München, Garching bei München, Germany.
  • 3 SciLifeLab, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
  • 4 Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 5 German Centre for Infection Research, Partner Site Braunschweig-Hannover, Hannover, Germany.
  • 6 Department of Chemistry, Temple University, Philadelphia, PA, USA.
  • 7 Center for Integrated Protein Science, TUM School of Life Sciences, Technische Universität München, Freising, Germany.
  • 8 Chair of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany.
  • 9 German Cancer Consortium, Partner Site Munich, Munich, Germany.
  • 10 German Cancer Research Center, Heidelberg, Germany.
  • 11 Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 12 Department of Chemistry, Technische Universität München, Garching bei München, Germany.
  • 13 Center for Integrated Protein Science Munich, Garching bei München, Germany.
  • 14 Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 15 Department of Chemistry, Emory University, Atlanta, GA, USA.
  • 16 Emory Antibiotic Resistance Center, Emory School of Medicine, Atlanta, GA, USA.
  • 17 Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 18 Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Garching bei München, Germany. stephan.sieber@tum.de.
  • 19 Chair of Organic Chemistry II, Technische Universität München, Garching bei München, Germany. stephan.sieber@tum.de.
  • 20 Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, Saarbrücken, Germany. stephan.sieber@tum.de.
  • # Contributed equally.
PMID: 31844194 DOI: 10.1038/s41557-019-0378-7
Abstract

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.

Figures
Products