Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1

Nature. 2007 Nov 29;450(7170):725-30. doi: 10.1038/nature06345.


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 pathways. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Cell Line, Tumor
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / microbiology*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Macrophages / drug effects
  • Macrophages / microbiology
  • Metabolic Networks and Pathways
  • Mice
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • Salmonella typhimurium / drug effects
  • Salmonella typhimurium / growth & development*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology


  • Anti-Bacterial Agents
  • Isoquinolines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Proto-Oncogene Proteins c-akt
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide