Deoxyribonucleoside kinases activate nucleoside antibiotics in severe pathogenic bacteria.
(2007) In Antimicrobial Agents and Chemotherapy 51(8). p.2726-2732- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/168060
- author
- Sandrini, Michael LU ; Shannon, Oonagh LU ; Clausen, Anders Ranegaard LU ; Björck, Lars LU and Piskur, Jure LU
- organization
- publishing date
- 2007
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Antimicrobial Agents and Chemotherapy
- volume
- 51
- issue
- 8
- pages
- 2726 - 2732
- publisher
- American Society for Microbiology
- external identifiers
-
- wos:000248523700010
- scopus:34547625777
- ISSN
- 1098-6596
- DOI
- 10.1128/AAC.00081-07
- language
- English
- LU publication?
- yes
- id
- a9a969d0-fd0c-46f4-8863-821e7baa8f8a (old id 168060)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17526755&dopt=Abstract
- date added to LUP
- 2016-04-01 17:02:18
- date last changed
- 2022-03-15 04:43:42
@article{a9a969d0-fd0c-46f4-8863-821e7baa8f8a, 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.}}, author = {{Sandrini, Michael and Shannon, Oonagh and Clausen, Anders Ranegaard and Björck, Lars and Piskur, Jure}}, issn = {{1098-6596}}, language = {{eng}}, number = {{8}}, pages = {{2726--2732}}, publisher = {{American Society for Microbiology}}, series = {{Antimicrobial Agents and Chemotherapy}}, title = {{Deoxyribonucleoside kinases activate nucleoside antibiotics in severe pathogenic bacteria.}}, url = {{http://dx.doi.org/10.1128/AAC.00081-07}}, doi = {{10.1128/AAC.00081-07}}, volume = {{51}}, year = {{2007}}, }