Nucleotides are needed as building blocks to manufacture DNA and RNA. Many pathogens lack important enzymes for nucleotide biosynthesis and are therefore dependent on nucleotide precursors (ribonucleosides, deoxynucleosides and bases), which can be taken up from the host organism. In the case of ribonucleosides and deoxynucleosides, they need to be phosphorylated in three steps before being usable as building blocks for RNA and DNA. We study the enzymes responsible for the first phosphorylating step.
Trypanosoma brucei is a unicellular parasite, which is spread by tsetse flies and causes the fatal disease African sleeping sickness. We exploit that the pathogen cannot perform de novo synthesis of adenosine (a ribonucleoside), which makes it dependent on the enzyme adenosine kinase to phosphorylate adenosine which is taken up from the blood. We exploit this weakness of the pathogen by developing substances (adenosine analogues), which resemble adenosine but kill the parasites after being activated by the enzyme.
The goal is to take advantage of the differences in the synthetic pathways in these pathogens compared to our own cells and thereby being able to identify drugs with minimized side effects.
Giardia lamblia and Borrelia burgdorferi are two organisms that lack ribonucleotide reductase, an enzyme needed for de novo biosynthesis of DNA building blocks. In this case, it is then the DNA building blocks (deoxynucleosides) that need to be taken up from the host and be phosphorylated. We study the enzymes needed for the phosphorylation of the deoxynucleosides and develop false substrates for these enzymes which upon activation harm the pathogens.
Giardia lamblia causes giardiasis, a serious diarrhea which can sometimes became fatal. Current treatments against giardiasis as well as African sleeping sickness can give serious side effects and are not always effective. The treatment options for borrelia looks better but also in this case there is a need to develop new medicines because of the increasing drug resistance. The substances developed here are designed to specifically target the intended pathogens and thereby limit the risk of interspecies spread of antibiotics resistance.