Research project The ultimate goals of the project are the identification of new drug targets and the development of new treatment strategies against pathogens with limited ability to make nucleotides and therefore need to take them up from the environment in the human body instead.
The project is financed by the Swedish Research Council 2020-22, 2023-25.
The ultimate goals of the project are the identification of new drug targets and the development of new treatment strategies against pathogens with limited ability to make nucleotides and therefore need to take them up from the environment in the human body instead.
The pathogens Giardia intestinalis and Borrelia burgdorferi cause giardiasis and borrelia, respectively. Both pathogens lack ribonucleotide reductase (RNR), an enzyme required for de novo synthesis of dNTP building blocks for DNA synthesis. The lack of RNR makes them vulnerable to drugs exploiting or targeting the compensatory salvage pathways needed to utilize dNTP precursors (deoxyribonucleosides) from the host. We characterize the kinases needed for this synthesis both via biochemical assays in vitro and via HPLC analysis of dNTPs in cells grown with different deoxyribonuclesosides. Drugs that are activated by the studied enzymes are tested against the pathogens in cell culture with mammalian cells as reference and subsequently in infected rodents.
It is not only RNR that is lacking in the two pathogens and there are many other limitations in the nucleotide metabolism, especially in G. intestinalis that also lacks de novo purine biosynthesis, de novo pyrimidine synthesis and de novo dTTP synthesis, and thereby has the most limited nucleotide metabolism of all organisms studied so far. Another protozoan pathogen which also has a very limited nucleotide metabolism is Trichomonas vaginialis and the research project is now expanded to also include this pathogen. T. vaginalis causes trichomoniasis, a venereal disease associated with infertility and cervical cancer.
