In this thesis we describe our work regarding the identification of novel biomarkers, host targets and candidate pharmacological compounds for the development of therapies against various... Show moreIn this thesis we describe our work regarding the identification of novel biomarkers, host targets and candidate pharmacological compounds for the development of therapies against various intracellular bacterial infections, focusing primarily on the interplaybetween tuberculosis and diabetes mellitus. We conducted two longitudinal cohort studies in South Africa and Indonesia, and we applied unbiased and selective transcriptomic approaches to identify novel biomarker profiles in tuberculosis patients with concomitant diabetes or hyperglycaemia. Further, we performed experiments with standardized in vitro cellular infection models for drug discovery. We identified potential host targets during Mycobacterium tuberculosis infections and we describe the role of central metabolic pathways bacterial infections in human macrophages. Show less
Antibiotic resistance is an increasing problem in the battle against (bacterial) infectious diseases. The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) threatens to render... Show moreAntibiotic 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. Show less
