Deoxyribonucleoside kinases activate nucleoside antibiotics in severe pathogenic bacteria.

Sandrini, MichaelLund University,Lunds universitet,Biologiska institutionen,Naturvetenskapliga fakulteten,Department of Biology,Faculty of Science (författare)

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.

Shannon, OonaghLund University,Lunds universitet,Infektionsmedicin,Sektion III,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Infection Medicine (BMC),Section III,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)med-osn (författare)
Clausen, Anders RanegaardLund University,Lunds universitet,Biologiska institutionen,Naturvetenskapliga fakulteten,Department of Biology,Faculty of Science(Swepub:lu)cob-asc (författare)
Björck, LarsLund University,Lunds universitet,Infektionsmedicin,Sektion III,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Infection Medicine (BMC),Section III,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)medk-lbj (författare)
Piskur, JureLund University,Lunds universitet,Molekylär cellbiologi,Biologiska institutionen,Naturvetenskapliga fakulteten,Molecular Cell Biology,Department of Biology,Faculty of Science(Swepub:lu)cob-jpi (författare)
Biologiska institutionenNaturvetenskapliga fakulteten (creator_code:org_t)

Av författaren/redakt...: Sandrini, Michae ...; Shannon, Oonagh; Clausen, Anders ...; Björck, Lars; Piskur, Jure

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Annan klinisk me ...

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