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Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11512-11517. doi: 10.1073/pnas.1706236114. Epub 2017 Oct 9.

Maladaptive DNA repair is the ultimate contributor to the death of trimethoprim-treated cells under aerobic and anaerobic conditions.

Author information

1
Faculté de Médecine Paris Descartes, INSERM U1001, Sorbonne Paris Cité, Université Paris Descartes, 75014 Paris, France.
2
Faculté de Médecine Paris Descartes, INSERM U1001, Sorbonne Paris Cité, Université Paris Descartes, 75014 Paris, France; ivan.matic@inserm.fr.
3
Department of Life Sciences, Centre National de la Recherche Scientifique, 75016 Paris, France.

Abstract

The bactericidal effects of antibiotics are undoubtedly triggered by target-specific interactions, but there is growing evidence that an important aspect of cytotoxicity results from treatment-induced metabolic perturbations. In this study, we characterized molecular mechanisms whereby trimethoprim treatment results in cell death, using Escherichia coli as the model organism. E. coli cells grown in rich medium that contained all amino acids and low amounts of thymidine were treated with trimethoprim under aerobic and anaerobic conditions. Under these growth conditions, accelerated thymine depletion is the primary trigger of the processes leading to cell death. Thymine depletion-induced DNA replication stress leads to the production of reactive oxygen species under aerobic conditions and of the DNA-damaging byproducts of nitrate respiration under anaerobic conditions. Lowering the DNA replication initiation rate by introducing the dnaA(Sx) allele or by overexpressing Hda protein reduces the number of active replication forks, which reduces the consumption of thymidine and increases resistance to trimethoprim under both aerobic and anaerobic conditions. Analysis of the involvement of DNA repair enzymes in trimethoprim-induced cytotoxicity clearly indicates that different amounts and/or different types of DNA lesions are produced in the presence or absence of oxygen. Maladaptive processing of the DNA damage by DNA repair enzymes, in particular by MutM and MutY DNA glycosylases, ultimately contributes to cell death.

KEYWORDS:

DNA repair; antibiotic; nitrate respiration; oxidative stress; trimethoprim

Comment in

PMID:
29073080
PMCID:
PMC5664507
DOI:
10.1073/pnas.1706236114
[Indexed for MEDLINE]
Free PMC Article

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