Deoxyribonucleoside kinases activate nucleoside antibiotics in severely pathogenic bacteria.
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.
Sandrini
Michael P B
MP
Department of Molecular Biology, University of Copenhagen, Universitetsparken 13, Copenhagen, Denmark. msandrini@aki.ku.dk
Shannon
Oonagh
O
Clausen
Anders R
AR
Björck
Lars
L
Piskur
Jure
J
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D013290:Streptococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D000093542:Gemcitabine
D000900:Anti-Bacterial Agents; D009705:Nucleosides; D003841:Deoxycytidine; D017853:Phosphotransferases (Alcohol Group Acceptor); C020018:deoxyribonucleoside kinases; D000093542:Gemcitabine