The Antibiotic Trimethoprim Displays Strong Mutagenic Synergy with 2-Aminopurine

Sara D'Souza; Justin E Miller; Jenny Ahn; Raechel Subandi; Daniel Lozano; James Ramirez; Marisa Goff; Christina Davidian; Jeffrey H Miller

doi:10.1128/AAC.01577-18

The Antibiotic Trimethoprim Displays Strong Mutagenic Synergy with 2-Aminopurine

Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01577-18. doi: 10.1128/AAC.01577-18. Print 2019 Feb.

Authors

Sara D'Souza^{1

2

3}, Justin E Miller^{1

2

3}, Jenny Ahn^{1

2

3}, Raechel Subandi^{1

2

3}, Daniel Lozano^{1

2

3}, James Ramirez^{1

2

3}, Marisa Goff^{1

2

3}, Christina Davidian^{1

2

3}, Jeffrey H Miller^{4

2

3}

Affiliations

¹ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA.
² Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA.
³ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
⁴ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA jhmiller@microbio.ucla.edu.

Abstract

We show that trimethoprim (TMP), an antibiotic in current use, displays a strong synergistic effect on mutagenesis in Escherichia coli when paired with the base analog 2-aminopurine (2AP), resulting in a 35-fold increase in mutation frequencies in the rpoB-Rif^r system. Combination therapies are often employed both as antibiotic treatments and in cancer chemotherapy. However, mutagenic effects of these combinations are rarely examined. An analysis of the mutational spectra of TMP, 2AP, and their combination indicates that together they trigger a response via an alteration in deoxynucleoside triphosphate (dNTP) ratios that neither compound alone can trigger. A similar, although less strong, response is seen with the frameshift mutagen ICR191 and 2AP. These results underscore the need for testing the effects on mutagenesis of combinations of antibiotics and chemotherapeutics.

Keywords: antibiotic; mutagenesis; synergy; trimethoprim.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

2-Aminopurine / pharmacology*
Anti-Bacterial Agents / pharmacology*
DNA-Directed RNA Polymerases / drug effects
Drug Synergism
Escherichia coli / drug effects
Escherichia coli / genetics*
Escherichia coli Proteins / drug effects
Mutagenesis / drug effects*
Mutagens / pharmacology*
Trimethoprim / pharmacology*

Substances

Anti-Bacterial Agents
Escherichia coli Proteins
Mutagens
rpoB protein, E coli
2-Aminopurine
Trimethoprim
DNA-Directed RNA Polymerases