Exploring ribonucleotide reductase as a target to combat bacterial infections


Funding source

Swedish Research Council - Vetenskapsrådet (VR)


Project Details

Start date: 01/01/2017
End date: 31/12/2019
Funding: 2100000 SEK


Description








We will search for novel antibiotics against human pathogens with the enzyme ribonucleotide reductase (RNR) as a target. RNR is essential to all free-living organisms and provides building blocks for DNA synthesis. RNR inhibition restricts the organism’s DNA replication, and consequently inhibits cell growth and proliferation. Few RNR inhibitors are used in anticancer and/or antiviral regimes.

We will utilize a newly discovered target in RNRs from the human pathogens Pseudomonas aeruginosa, the major cause of mortality in cystic fibrosis patients, and Clamydia trachomatis, responsible for the most prevalent sexually transmitted disease worldwide and the single most important infectious agent associated with blindness (trachoma). Interestingly, this newly discovered target, which is an allosteric ATP-cone that binds two dATP molecules as opposed to multicellular eukaryotic RNRs, including human RNR, that bind only one dATP molecule, may be more prevalent than originally thought as judged from our bioinformatics comparisons. We will use both designed synthesis of di-dATP analogs and high-throughput screening for new RNR inhibitors using one of two novel HTS RNR assays recently developed.

Infectious diseases cause 25% of all deaths in the world with increasing multidrug resistant pathogens. On a long-term perspective, we plan to adopt the assay to RNRs from several multidrug resistant pathogens, e.g. Bacillus anthracis, Francisella spp. and Streptococcus pyogenes.









Last updated on 2017-04-10 at 11:57