Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1.
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.
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Coenraad
C
Kuijl
Nigel D L
ND
Savage
Marije
M
Marsman
Adriaan W
AW
Tuin
Lennert
L
Janssen
David A
DA
Egan
Mirjam
M
Ketema
Rian
R
van den Nieuwendijk
Susan J F
SJ
van den Eeden
Annemieke
A
Geluk
Alex
A
Poot
Gijs
G
van der Marel
Roderick L
RL
Beijersbergen
Hermen
H
Overkleeft
Tom H M
TH
Ottenhoff
Jacques
J
Neefjes
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000382:microbiology*; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D053858:Metabolic Networks and Pathways; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D051057:Proto-Oncogene Proteins c-akt; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide