Antimicrobial susceptibility and SOS-dependent increase in mutation frequency are impacted by Escherichia coli topoisomerase I C-terminal point mutation

Jenny Yang, Thirunavukkarasu Annamalai, Bokun Cheng, Srikanth Banda, Rakhi Tyagi, Yuk Ching Tse-Dinh

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Topoisomerase functions are required in all organisms for many vital cellular processes, including transcription elongation. The C terminus domains (CTD) of Escherichia coli topoisomerase I interact directly with RNA polymerase to remove transcription-driven negative supercoiling behind the RNA polymerase complex. This interaction prevents inhibition of transcription elongation from hypernegative supercoiling and R-loop accumulation. The physiological function of bacterial topoisomerase I in transcription is especially important for a rapid network response to an antibiotic challenge. In this study, Escherichia coli with a topA66 single nucleotide deletion mutation, which results in a frameshift in the TopA CTD, was shown to exhibit increased sensitivity to trimethoprim and quinolone antimicrobials. The topoisomerase I-RNA polymerase interaction and the SOS response to the antimicrobial agents were found to be significantly reduced by this topA66 mutation. Consequently, the mutation frequency measured by rifampin selection following SOS induction was diminished in the topA66 mutant. The increased antibiotic sensitivity for the topA66 mutant can be reversed by the expression of recombinant E. coli topoisomerase I but not by the expression of recombinant Mycobacterium tuberculosis topoisomerase I that has a nonhomologous CTD even though the recombinant M. tuberculosis topoisomerase I can restore most of the plasmid DNA linking number deficiency caused by the topA66 mutation. Direct interactions of E. coli topoisomerase I as part of transcription complexes are likely to be required for the rapid network response to an antibiotic challenge. Inhibitors of bacterial topoisomerase I functions and interactions may sensitize pathogens to antibiotic treatment and limit the mutagenic response.

Original languageEnglish (US)
Pages (from-to)6195-6202
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number10
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

Fingerprint

Type I DNA Topoisomerase
Mutation Rate
Point Mutation
Escherichia coli
DNA-Directed RNA Polymerases
Anti-Bacterial Agents
Mycobacterium tuberculosis
Topoisomerase I Inhibitors
Mutation
Trimethoprim
Sequence Deletion
Quinolones
Rifampin
Anti-Infective Agents
Plasmids
Nucleotides
DNA

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Antimicrobial susceptibility and SOS-dependent increase in mutation frequency are impacted by Escherichia coli topoisomerase I C-terminal point mutation. / Yang, Jenny; Annamalai, Thirunavukkarasu; Cheng, Bokun; Banda, Srikanth; Tyagi, Rakhi; Tse-Dinh, Yuk Ching.

In: Antimicrobial Agents and Chemotherapy, Vol. 59, No. 10, 01.10.2015, p. 6195-6202.

Research output: Contribution to journalArticle

Yang, Jenny ; Annamalai, Thirunavukkarasu ; Cheng, Bokun ; Banda, Srikanth ; Tyagi, Rakhi ; Tse-Dinh, Yuk Ching. / Antimicrobial susceptibility and SOS-dependent increase in mutation frequency are impacted by Escherichia coli topoisomerase I C-terminal point mutation. In: Antimicrobial Agents and Chemotherapy. 2015 ; Vol. 59, No. 10. pp. 6195-6202.
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