Fumarate-mediated persistence of Escherichia coli against antibiotics

Jun Seob Kim, Da Hyeong Cho, Paul Heo, Suk Chae Jung, Myungseo Park, Eun Joong Oh, Jaeyun Sung, Pan Jun Kim, Suk Chan Lee, Dae Hee Lee, Sarah Lee, Choong Hwan Lee, Dongwoo Shin, Yong Su Jin, Dae Hyuk Kweon

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Bacterial persisters are a small fraction of quiescent cells that survive in the presence of lethal concentrations of antibiotics. They can regrow to give rise to a new population that has the same vulnerability to the antibiotics as did the parental population. Although formation of bacterial persisters in the presence of various antibiotics has been documented, the molecular mechanisms by which these persisters tolerate the antibiotics are still controversial. We found that amplification of the fumarate reductase operon (FRD) in Escherichia coli led to a higher frequency of persister formation. The persister frequency of E. coli was increased when the cells contained elevated levels of intracellular fumarate. Genetic perturbations of the electron transport chain (ETC), a metabolite supplementation assay, and even the toxin-antitoxin-related hipA7 mutation indicated that surplus fumarate markedly elevated the E. coli persister frequency. An E. coli strain lacking succinate dehydrogenase (SDH), thereby showing a lower intracellular fumarate concentration, was killed ∼ 1,000-fold more effectively than the wild-type strain in the stationary phase. It appears that SDH and FRD represent a paired system that gives rise to and maintains E. coli persisters by producing and utilizing fumarate, respectively.

Original languageEnglish (US)
Pages (from-to)2232-2240
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number4
DOIs
StatePublished - Apr 2016

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Kim, J. S., Cho, D. H., Heo, P., Jung, S. C., Park, M., Oh, E. J., Sung, J., Kim, P. J., Lee, S. C., Lee, D. H., Lee, S., Lee, C. H., Shin, D., Jin, Y. S., & Kweon, D. H. (2016). Fumarate-mediated persistence of Escherichia coli against antibiotics. Antimicrobial Agents and Chemotherapy, 60(4), 2232-2240. https://doi.org/10.1128/AAC.01794-15