Deoxyribonucleoside kinases activate nucleoside antibiotics in severely pathogenic bacteria

Michael Sandrini, O. Shannon, A.R. Clausen, L. Bjorck, Jure Piskur

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    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.
    Original languageEnglish
    JournalAntimicrobial Agents and Chemotherapy
    Volume51
    Issue number8
    Pages (from-to)2726-2732
    ISSN0066-4804
    DOIs
    Publication statusPublished - 2007

    Fingerprint Dive into the research topics of 'Deoxyribonucleoside kinases activate nucleoside antibiotics in severely pathogenic bacteria'. Together they form a unique fingerprint.

    Cite this