Antibiotic
resistance is an increasing problem in the battle against (bacterial)
infectious diseases. The emergence of drug-resistant Mycobacterium tuberculosis
(Mtb) threatens to render tuberculosis (TB) untreatable. Efforts to develop
novel antibiotics have so far been unsuccessful, calling for additional
approaches for treatment of bacterial infections. Intracellular pathogens like
Mtb and Salmonella can survive in the host by manipulating host cell signaling.
This provides opportunities for novel therapeutic strategies by targeting the
host, rather than the bacterium (host-directed therapy).
In this thesis we report the development and application of novel (in vitro and
in vivo) methods for identifying host genes and proteins involved in host
control of intracellular bacteria, as well as chemical compounds that target
host molecules as a basis for drug development for host-directed therapies. As
a result, we report the identification of RTK inhibitors, the novel kinase
inhibitor 97i, the human kinase family PCTAIRE and the host protein DRAM1 as
promising leads for further drug development for host-directed therapeutic
strategies for intracellular bacterial infections.LUMC / Geneeskund