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.
Kuijl
Coenraad
C
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Savage
Nigel D L
ND
Marsman
Marije
M
Tuin
Adriaan W
AW
Janssen
Lennert
L
Egan
David A
DA
Ketema
Mirjam
M
van den Nieuwendijk
Rian
R
van den Eeden
Susan J F
SJ
Geluk
Annemieke
A
Poot
Alex
A
van der Marel
Gijs
G
Beijersbergen
Roderick L
RL
Overkleeft
Hermen
H
Ottenhoff
Tom H M
TH
Neefjes
Jacques
J
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