Exploring ribonucleotide reductase as a target to combat bacterial infections


Project leader


Funding source

Swedish Research Council - Vetenskapsrådet (VR)


Project Details

Start date: 01/01/2011
End date: 31/12/2013
Funding: 2700000 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. A few RNR inhibitors are used primarily in anticancer regimes. We will use high-throughput screening for new RNR inhibitors with a diverse chemical library (ca. 2,000 substances from a master library of >100,000 compounds) that we have received free-of-charge from the US National Cancer Institute. To accomplish this we have developed a new high-throughput assay for RNR enzyme activity that, in contrast to available assays, is quick (a few hours), easy (mix-incubate-mix-measure), and suitable for multi-well formats and laboratory robotics. We will initially screen RNRs from the human pathogens Pseudomonas aeruginosa, the major cause of mortality in cystic fibrosis patients, and Bacillus anthracis, causing inhalation anthrax. In a preliminary screen for inhibition of pathogen growth we identified a P. aeruginosa biofilm inhibitor (proof-of-principle), and 3 different inhibitors of P. aeruginosa RNR. Several inhibitors of B. anthracis growth were identified. We will check the inhibitors´ properties and suitability as lead compounds in further analyses. Infectious diseases cause 25% of all deaths in the world with increasing multidrug resistant pathogens.

Last updated on 2017-31-03 at 12:57