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Deoxyribonucleoside kinases activate nucleoside antibiotics in severe pathogenic bacteria.

Sandrini, Michael LU ; Shannon, Oonagh LU ; Clausen, Anders Ranegaard LU ; Björck, Lars LU and Piskur, Jure LU (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)
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author
organization
publishing date
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
2007-07-12 15:02:37
date last changed
2017-08-20 04:32:43
@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},
  volume       = {51},
  year         = {2007},
}