1. Division of Tumor Biology, and,
2. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
3. Department of Immunohematology and Blood Transfusion and Department of Infectious Diseases, Leiden Medical University Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
4. Department of Bioorganic Chemistry, Leiden Institute of Chemistry, 2300 RA Leiden, The Netherlands

Correspondence to: Jacques Neefjes¹ Correspondence and requests for materials should be addressed to J.N. (Email: j.neefjes@nki.nl).

Abstract

With the emergence of multidrug resistant (MDR) bacteria, it is imperative to develop new intervention strategies. Current antibiotics typically target pathogen rather than host-specific biochemical pathways¹. Here we have developed kinase inhibitors that prevent intracellular growth of unrelated pathogens such as Salmonella typhimurium and Mycobacterium tuberculosis. An RNA interference screen of the human kinome using automated microscopy revealed several host kinases capable of inhibiting intracellular growth of S. typhimurium. The kinases identified clustered in one network around AKT1 (also known as PKB). Inhibitors of AKT1 prevent intracellular growth of various bacteria including MDR-M. tuberculosis. AKT1 is activated by the S. typhimurium effector SopB, which promotes intracellular survival by controlling actin dynamics through PAK4, and phagosome–lysosome fusion through the AS160 (also known as TBC1D4)–RAB14 pathway. AKT1 inhibitors counteract the bacterial manipulation of host signalling processes, thus controlling intracellular growth of bacteria. By using a reciprocal chemical genetics approach, we identified kinase inhibitors with antibiotic properties and their host targets, and we determined host signalling networks that are activated by intracellular bacteria for survival.

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