(Z)-4-Bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one sensitizes Escherichia coli persister cells to antibiotics

• Published in: Applied microbiology and biotechnology 2013-10, Vol.97 (20), p.9145-9154
• Main Authors: Pan, Jiachuan, Xie, Xin, Tian, Wang, Bahar, Ali Adem, Lin, Nan, Song, Fangchao, An, Jing, Ren, Dacheng
• Format: Article
• Language: English
• Subjects: 3T3 Cells; 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; Antibiotic tolerance; Antibiotics; Applied Microbial and Cell Physiology; Bacteria; Bacterial infections; Biofilms; Biofilms - drug effects; Biomedical and Life Sciences; Biotechnology; Cell Line; Cell Survival - drug effects; Cytotoxicity; Drug resistance; Drug Resistance, Bacterial; E coli; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - growth & development; Escherichia coli - physiology; Humans; Life Sciences; Mice; Mice, Inbred C57BL; Microbial Genetics and Genomics; Microbial Sensitivity Tests; Microbiology; Quorum Sensing - drug effects; Toxins
• ISSN: 0175-7598; 1432-0614
• DOI: 10.1007/s00253-013-5185-2

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(5 H )-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.