(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.

Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments

“…Moreover, halogenated indoles have been observed to remove bacterial biofilms and persistent cells formed by Gram-positive and Gram-negative microorganisms, such as S. aureus and E. coli (226). Pan et al demonstrated that the QS inhibitor BF8 decreases the persistence of growing E. coli cultures and throwback antibiotic tolerance in the persisters (442). The benzimidazole derivative M64 is another QS inhibitor that has been described in relation to preventing the development of persister cells, by blocking the PqsR QS/virulence system of P. aeruginosa (441).…”

Strategies to Combat Persistent Infectious Diseases

“…Antivirulence treatment targets bacterial virulence without interfering with their growth. In 2013, Pan et al [35] characterized a chemical compound called BF8 ((Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one) able to reduce persistence during E. coli growth and revert the antibiotic tolerance of persisters. This BF8 is a QS inhibitor of E. coli which disrupted E. coli biofilms and rendered associated cells more sensitive to ofloxacin.…”

The role of metabolism in bacterial persistence

“…However, upon further analysis, it was discovered that the effect of BF8 was likely due to reactivation of metabolism rather than inhibition of QS. Interestingly, BF8 has also been found to reduce E. coli persister levels when combined with OFL, tetracycline (TET), TOB, or GEN (Pan et al, 2013). Recently, another method to eliminate S. aureus persisters was discovered by leveraging knowledge that energy levels are low in persisters (Conlon et al, 2013).…”