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Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides

S W Mamber1, K W Brookshire, S Forenza

  • 1Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Wallingford, Connecticut 06492-7440.

Antimicrobial Agents and Chemotherapy
|June 1, 1990
PubMed

Insights

The SOS response in E. coli can be induced by anti-HIV nucleosides like azidothymidine (AZT) and dideoxynucleosides, suggesting bacterial assays are useful for discovering new HIV treatments.

Area of Science:

  • Microbiology
  • Virology
  • Drug Discovery

Background:

  • Human immunodeficiency virus (HIV) remains a significant global health challenge.
  • Nucleoside analogs are a cornerstone of antiretroviral therapy.
  • Understanding the mechanisms of action and potential toxicities of these agents is crucial.

Purpose of the Study:

  • To evaluate the ability of various anti-HIV nucleosides to induce the SOS response in Escherichia coli.
  • To assess the utility of bacterial SOS response assays as a prescreen for novel anti-HIV agents.
  • To investigate the relationship between chemical structure and SOS-inducing activity.

Main Methods:

  • Colorimetric (beta-galactosidase) assays were employed to measure SOS induction in E. coli.
  • Two assay formats were used: agar diffusion and liquid microsuspension.
  • Specific nucleosides tested included azidothymidine (AZT), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxythymidine (ddT), 2',3'-dideoxy-2',3'-didehydrothymidine (D4T), and 2',3'-dideoxycytidine (ddC).

Main Results:

  • Azidothymidine (AZT) was the most potent inducer of the SOS response, approximately 100 times more active than dideoxypurine nucleosides.
  • Dideoxypurine nucleosides (ddA, ddG, ddI) induced the SOS response, with varying potencies.
  • ddT and D4T showed moderate SOS-inducing activity, while ddC had weak activity.
  • AZT and ddA demonstrated marginal effects in DNA repair assays, suggesting their primary mechanism is not DNA lesion induction.
  • Observed differences in activity between agar diffusion and liquid microsuspension assays for ddA and ddI may relate to drug metabolism.

Conclusions:

  • The SOS response in E. coli is induced by anti-HIV nucleosides, likely through DNA chain termination and inhibition of DNA replication, rather than DNA damage.
  • Bacterial SOS response assays serve as effective, rapid prescreens for identifying new anti-HIV drug candidates.
  • These assays can provide valuable supplementary data for evaluating antiretroviral agents.

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