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Antimicrobial Agents and Chemotherapy, August 2007, p. 2726-2732, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00081-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Deoxyribonucleoside Kinases Activate Nucleoside Antibiotics in Severely Pathogenic Bacteria{triangledown}

Michael P. B. Sandrini,1,2* Oonagh Shannon,3 Anders R. Clausen,2 Lars Björck,3 and Jure Piskur2

BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark,1 Cell and Organism Biology, Lund University, Sölvegatan 35, SE-22362 Lund, Sweden,2 Section for Clinical and Experimental Infection Medicine, BMC, B14, Lund University, Tornavägen 10, SE-22184 Lund, Sweden3

Received 19 January 2007/ Returned for modification 6 March 2007/ Accepted 21 May 2007

Common bacterial pathogens are becoming progressively more resistant to traditional antibiotics, representing a major public-health crisis. Therefore, there is a need for a variety of antibiotics with alternative modes of action. In our study, several nucleoside analogs were tested against pathogenic staphylococci and streptococci. We show that pyrimidine-based nucleoside analogs, like 3'-azido-3'-deoxythymidine (AZT) and 2',2'-difluoro-2'deoxycytidine (gemcitabine), are specifically activated by the endogenous bacterial deoxyribonucleoside kinases, leading to cell death. Deoxyribonucleoside kinase-deficient Escherichia coli strains become highly susceptible to nucleoside analogs when they express recombinant kinases from Staphylococcus aureus or Streptococcus pyogenes. We further demonstrate that recombinant S. aureus deoxyadenosine kinase efficiently phosphorylates the anticancer drug gemcitabine in vitro and is therefore the key enzyme in the activation pathway. When adult mice were infected intraperitoneally with a fatal dose of S. pyogenes strain AP1 and afterwards received gemcitabine, they failed to develop a systemic infection. Nucleoside analogs may therefore represent a promising alternative for combating pathogenic bacteria.

* Corresponding author. Present address: Department of Molecular Biology, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen, Denmark. Phone: 45 3532 1734. Fax: 45 3532 1567. E-mail: msandrini{at}aki.ku.dk

{triangledown} Published ahead of print on 25 May 2007.

Antimicrobial Agents and Chemotherapy, August 2007, p. 2726-2732, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00081-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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