The focus of our research is the validation of promising drug targets for subsequent development of active compounds (antibiotics) for disease treatment. We are particularly interested in Glutamine synthetase-like enzymes as promising drug targets. We investigate nitrogen metabolism in Actinobacteria like Streptomyces coelicolor (actinobacterial model organism) and Mycobacterium tuberculosis (tuberculosis pathogen), focusing on polyamine and monoamine metabolism. Our studies on polyamine and ethanolamine utilization pathways as well on characterizations of GS-like enzymes allow design and development of new compounds for treatment of tuberculosis and other mycobacterial infections.
- GSS-TUBTAR: Validation of the confirmed γ-glutamylspermine synthetase GlnA3 as a target for development of novel anti-tubercular drugs (BMBF, 2020-2022)
- GPS-TBT: Validation of the γ-glutamylpolyamine synthetase GlnA3Mt as a promising target for development of novel anti-tubercular drugs (BMBF, 2018-2020)
- Characterization of polyamine and ethanolamine utilization pathways in Streptomyces coelicolor M145 (DFG, GRK1708 (I and II), 2015-2018)
Despite the availability of a therapy, tuberculosis (TB) remains a disease difficult to treat that affects persons in both high-income and developing countries worldwide. The latest status of the tuberculosis is epidemic, which raises the urgent need for discovery of novel anti-TB drugs to treat TB as well as rapidly emerging multidrug-resistant tuberculosis (MDR-TB). The project GSS-TUBTAR aims to validate the gamma-glutamylspermine synthetase GlnA3Mt as a novel drug target for pharmaceutical development of novel active compounds. Recent investigations have revealed that Mycobacterium tuberculosis (MTB) requires a special mechanism to detoxify specifically the polyamine spermine in order to survive in human macrophages. This detoxification is achieved by glutamylation of spermine catalyzed by the enzyme GlnA3Mt. Based on the biochemical, genetic and structural features of GlnA3Mt, inhibitors of the enzyme will be developed and optimized to prevent its detoxifying activity. Since gamma-glutamylspermine synthetases are not present in human cells, GlnA3Mt is a promising and safe target to treat tuberculosis as well as other mycobacterial infections. Targeting the MTB spermine metabolism may result in prevention of spermine detoxification. High (toxic) amounts of spermine accumulated intracellularly will support the natural immune response of the host (spermine production in human lungs) leading to eradication of the infection. In GSS-TUBTAR, a multi-validation approach integrates the following approaches: genetics, structure biology, bioinformatics, biochemistry, synthetic chemistry, cell biology. Pharmacological proof of concept will be delivered by proving the ligandability, druggability and selectivity of the target.