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

• Type of Material: Article
• Authors: Philipp Le, Technical University of Munich; Elena Kunold, Technical University of Munich; Robert Macsics, Technical University of Munich; Katharina Rox, Helmholtz Centre for Infection Research; Megan C. Jennings, Temple University; Ilke Ugur, Technical University of Munich; Maria Reinecke, Technical University of Munich; Diego Chaves-Moreno, Helmholtz Centre for Infection Research; Mathias W. Hackl, Technical University of Munich; Christian Fetzer, Technical University of Munich; Franziska A. M. Mandl, Technical University of Munich; Johannes Lehmann, Technical University of Munich; Vadim S. Korotkov, Technical University of Munich; Stephan M. Hacker, Technical University of Munich; Bernhard Kuster, Technical University of Munich; Iris Antes, Technical University of Munich; Dietmar H. Pieper, Helmholtz Centre for Infection Research; Manfred Rohde, Helmholtz Centre for Infection Research; William Wuest, Emory University; Eva Medina, Helmholtz Centre for Infection Research; Stephan A. Sieber, Technical University of Munich
• Language: English
• Date: 2020-02-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © The Author(s), under exclusive licence to Springer Nature Limited 2019.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41557-019-0378-7
• Title of Journal or Parent Work: Nature Chemistry
• Volume: 12
• Issue: 2
• Start Page: 145
• End Page: +
• Grant/Funding Information: S.M.H. acknowledges financial support by a Liebig fellowship of the Fonds der Chemischen Industrie.; S.A.S. was funded by the Center for Integrated Protein Science Munich (CIPSM), Deutsche Forschungsgemeinschaft SFB1035 and European Research Council (ERC) and the European Union’s Horizon 2020 research and innovation programme (grant agreement No 725085, CHEMMINE, ERC consolidator grant).; R.M. was supported by a doctoral fellowship of the Boehringer Ingelheim Fonds.; I.A. acknowledges funding by Deutsche Forschungsgemeinschaft SFB1035. W.M.W. was funded by National Science Foundation (CHE-1454116) and the National Institute of General Medical Sciences (R35 GM119426). javascript:void(0); E.K. was supported by the doctoral fellowship of the Fonds der Chemischen Industrie.; M.W.H., C.F. and F.A.M.M. were funded by the Federal Ministry for Education and Research (BMBF) under the framework programme ‘VIP+’ – project ‘aBacter’.; K.R. was supported by the German Centre for Infection Research (DZIF) (TTU 09.710).; M.C.J. acknowledges a National Science Foundation predoctoral grant (DGE-1144462).
• Keywords: Proteome; Expression; Infections; Identification; Chemistry, Multidisciplinary; Membrane; Growth; Mechanisms; Science & Technology; Physical Sciences; CLPP; I Signal peptidase; Menaquinone-7; Chemistry
• Research Categories: Chemistry, Biochemistry; Health Sciences, Immunology; Chemistry, Organic; Chemistry, Pharmaceutical

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.