Research project Exploring ribonucleotide reductase as a target to combat bacterial infections

RNR inhibition restricts the organism´s DNA replication, and consequently inhibits cell growth and proliferation. Few RNR inhibitors are currently used in antimicrobial regimes.

We will utilize the allosteric ATP-cone as a target in RNRs from the human pathogens Pseudomonas aeruginosa and Chlamydia trachomatis. We will also explore the bacterial RNR-specific transcription factor NrdR as a target for inhibition of bacterial pathogens. In addition, we will delineate the mechanisms by which radical cofactors are generated in RNRs with a metal-free DOPA (3,4-dihydroxyphenylalanine) radical and RNRs with a Mn(IV)/Mn(III) radical. RNRs in Mycoplasmas and Streptococcus pyogenes belong to the first group; Facklamia ignava and the emerging hospital pathogen Elizabethkingia spp RNRs belong to the second group.

Infectious diseases cause 25% of all deaths in the world with increasing multidrug resistant pathogens. The ATP-cones and the specific radical cofactors in the pathogens differ distinctly from corresponding counterparts in human RNR, and the NrdR regulator is only found in bacteria. They are potential targets for antibacterial screens. On a long-term perspective, we will study RNRs from other multidrug resistant pathogens, e.g. Bacillus anthracis and Francisella spp.