Deoxyribonucleoside kinases activate nucleoside antibiotics in severely pathogenic bacteria
Michael P B Sandrini1, Oonagh Shannon, Anders R Clausen
1Department of Molecular Biology, University of Copenhagen, Universitetsparken 13, Copenhagen, Denmark. msandrini@aki.ku.dk
Antimicrobial Agents and Chemotherapy
|May 29, 2007
Summary
Pyrimidine nucleoside analogs, like gemcitabine, show promise as novel antibiotics. Bacterial kinases activate these compounds, leading to pathogen cell death and protection in animal models against deadly infections.
Area of Science:
- Microbiology
- Drug Discovery
- Biochemistry
Background:
- Antibiotic resistance in common bacterial pathogens poses a significant public health threat.
- Novel antibiotics with alternative mechanisms of action are urgently needed.
- Nucleoside analogs are a potential class of antimicrobial agents.
Purpose of the Study:
- To investigate the efficacy of pyrimidine-based nucleoside analogs against pathogenic bacteria.
- To elucidate the activation mechanism of nucleoside analogs by bacterial enzymes.
- To evaluate the therapeutic potential of gemcitabine in a preclinical bacterial infection model.
Main Methods:
- Testing pyrimidine nucleoside analogs against Staphylococcus and Streptococcus species.
- Assessing the role of bacterial deoxyribonucleoside kinases in nucleoside analog activation using engineered E. coli strains.
- In vitro enzymatic assays using recombinant Staphylococcus aureus deoxyadenosine kinase.
- Evaluating gemcitabine efficacy in a mouse model of Streptococcus pyogenes infection.
Main Results:
- Pyrimidine nucleoside analogs, including 3'-azido-3'-deoxythymidine (AZT) and gemcitabine, were activated by bacterial deoxyribonucleoside kinases, leading to bacterial cell death.
- Deoxyribonucleoside kinase-deficient E. coli became susceptible to nucleoside analogs upon expression of recombinant kinases from S. aureus or S. pyogenes.
- Recombinant S. aureus deoxyadenosine kinase efficiently phosphorylated gemcitabine in vitro, identifying it as a key enzyme in the activation pathway.
- Gemcitabine administration protected mice from a fatal S. pyogenes infection.
Conclusions:
- Bacterial deoxyribonucleoside kinases are crucial for activating pyrimidine nucleoside analogs.
- Gemcitabine, activated by bacterial kinases, demonstrates potent antimicrobial activity and therapeutic efficacy in vivo.
- Nucleoside analogs represent a promising new avenue for developing antibiotics against resistant bacterial pathogens.
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