Open AccessDeoxyribonucleoside Kinases Activate Nucleoside Antibiotics in Severely Pathogenic Bacteria
Author(s) -
Michael Sandrini,
Oonagh Shan,
Anders R. Clausen,
Lars Björck,
Jure Piškur
Publication year - 2007
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00081-07
Subject(s) - nucleoside , nucleoside analogue , deoxycytidine kinase , kinase , microbiology and biotechnology , streptococcus pyogenes , antibiotics , biology , deoxyribonucleoside , pathogenic bacteria , staphylococcus aureus , gemcitabine , biochemistry , bacteria , enzyme , deoxycytidine , cancer , genetics
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-deficientEscherichia coli strains become highly susceptible to nucleoside analogs when they express recombinant kinases fromStaphylococcus aureus orStreptococcus pyogenes . We further demonstrate that recombinantS. 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 ofS. 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.