Fumarate-Mediated Persistence of Escherichia coli against Antibiotics

• Published in: Antimicrobial agents and chemotherapy 2016-04, Vol.60 (4), p.2232-2240
• Main Authors: Kim, Jun-Seob, Cho, Da-Hyeong, Heo, Paul, Jung, Suk-Chae, Park, Myungseo, Oh, Eun-Joong, Sung, Jaeyun, Kim, Pan-Jun, Lee, Suk-Chan, Lee, Dae-Hee, Lee, Sarah, Lee, Choong Hwan, Shin, Dongwoo, Jin, Yong-Su, Kweon, Dae-Hyuk
• Format: Article
• Language: English
• Subjects: Ampicillin - pharmacology; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Bacterial Proteins; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Citric Acid Cycle - drug effects; Citric Acid Cycle - genetics; Drug Resistance, Multiple, Bacterial; Drug Resistance, Multiple, Bacterial - genetics; Electron Transport - drug effects; Electron Transport - genetics; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli - genetics; Fumarates - metabolism; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Gene Library; Kanamycin - pharmacology; Microbial Sensitivity Tests; Norfloxacin - pharmacology; Operon; Succinate Dehydrogenase; Succinate Dehydrogenase - deficiency; Succinate Dehydrogenase - genetics; Susceptibility
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.01794-15

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) inEscherichia coliled to a higher frequency of persister formation. The persister frequency ofE. coliwas 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-relatedhipA7mutation indicated that surplus fumarate markedly elevated theE. colipersister frequency. AnE. colistrain 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 thatSDHandFRDrepresent a paired system that gives rise to and maintainsE. colipersisters by producing and utilizing fumarate, respectively.