Deoxyribonucleoside kinases activate nucleoside antibiotics in severe pathogenic bacteria.

Summary, in English

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.

• Author: Michael Sandrini; Oonagh Shannon; Anders Ranegaard Clausen; Lars Björck; Jure Piskur
• Department/s: Department of Biology; Infection Medicine (BMC); Molecular Cell Biology
• Publishing year: 2007
• Language: English
• Pages: 2726-2732
• Publication/Series: Antimicrobial Agents and Chemotherapy
• Volume: 51
• Issue: 8
• Links: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17526755&dopt=Abstract; http://dx.doi.org/10.1128/AAC.00081-07
• Document type: Journal article
• Publisher: American Society for Microbiology
• Topic: Other Clinical Medicine; Infectious Medicine
• Status: Published
• ISBN/ISSN/Other: ISSN: 1098-6596