Targeting three human pathogens that are lacking an essential enzyme

The pathogens Giardia intestinalis Borrelia burgdorferi and Trichomonas vaginalis cause giardiasis, borrelia and trichomoniasis, respectively.

All three pathogens lack ribonucleotide reductase (RNR), an enzyme that is essential in nearly all organisms and is required for de novo synthesis of dNTP building blocks used for DNA synthesis.

Our hypothesis is that the lack of RNR makes it necessary to have efficient compensatory salvage pathways needed to utilize the ultralow levels of dNTP precursors (deoxynucleosides) present in the host, and that the pathogens should be vulnerable to drugs that target or exploit these pathways.

The suggested experiments include biochemical assays on the recombinantly expressed salvage enzymes as well as dNTP analyses of pathogens grown in the presence of labeled or unlabeled dNTP precursors to reveal how the cellular metabolism in the pathogens is optimized for an efficient salvage (year 1-3).

In parallel, drugs mimicking the natural substrates will be tested on the purified enzymes and in cell culture with mammalian cells as reference and finally evaluated in infected rodents (year 4-5). Most experiments are performed here except the animal studies, which are currently performed by our collaborators.

Results obtained so far indicates that it is a successful strategy to identify new drug candidates, which is highly needed because current treatments do not work in all patients and side effects are common.