title: (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one sensitizes Escherichia coli persister cells to antibiotics.
abstract: Persisters are a small subpopulation of bacterial cells that are dormant and extremely tolerant to antibiotics. The intrinsic antibiotic tolerance of persisters also facilitates the development of multidrug resistance through acquired mechanisms based on drug resistance genes. In this study, we demonstrate that (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one (BF8) can reduce persistence during Escherichia coli growth and revert the antibiotic tolerance of its persister cells. The effects of BF8 were more profound when the pH was increased from 6 to 8.5. Although BF8 is a quorum sensing (QS) inhibitor, similar effects were observed for the wild-type E. coli RP437 and its ΔluxS mutant, suggesting that these effects did not occur solely through inhibition of AI-2-mediated QS. In addition to its effects on planktonic persisters, BF8 was also found to disperse RP437 biofilms and to render associated cells more sensitive to ofloxacin. At the doses that are effective against E. coli persister cells, BF8 appeared to be safe to the tested normal mammalian cells in vitro and exhibited no long-term cytotoxicity to normal mouse tissues in vivo. These findings broadened the activities of brominated furanones and shed new light on persister control.
authors.affiliation: Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, NY, 13244, USA.
authors.forename: Jiachuan
authors.initials: J
authors.lastname: Pan
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Wang
authors.initials: W
authors.lastname: Tian
authors.forename: Ali Adem
authors.initials: AA
authors.lastname: Bahar
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: Fangchao
authors.initials: F
authors.lastname: Song
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.forename: Dacheng
authors.initials: D
authors.lastname: Ren
mesh_terms: D016475:3T3 Cells; D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D053038:Quorum Sensing / Q000187:drug effects
chemical_list: C578511:4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one; D000900:Anti-Bacterial Agents; D015107:4-Butyrolactone