Synthetic furanones and inhibition of biofilm formation
AbstractIn this study we investigated whether furanones could prevent biofilms from being formed. Our first aim was to find a new synthesis pathway for (Z)-5-bromomethylene-2(5H)-furanone, a furanone also produced in nature by the macro-alga Delisa pulchra, and to investigate its effects on biofilm formation by Streptococcus anginosus, Streptococcus intermedius, Streptococcus mutans and Staphylococcus epidermidis. We also synthesised 5- (bromomethylene)furan-2(5H)-ones and 3-(bromomethylene)isobenzofuran-1(3H)-ones to further investigate their effects on biofilm formation by S. epidermidis. The effect on biofilm formation was assessed either by adding furanone to the growth medium or by allowing biofilm to form on surface-adsorbed furanone. Furanone effectively decreased biofilm formation by both application methods, but with surface-adsorbed furanone being most effective. The furanone concentrations used had no effect on microbial growth, and were also well below the established MICs, indicating that the effect was not a result of an antimicrobial effect. In order to determine whether the inhibitory effect was associated with the ability of furanone to interfere with microbial AI-2 communication, AI-2 deficient mutants were included. In contrast to their wild types, the amount of biofilm formed by the communication defective S. anginosus and S. intermedius was not affected when adding furanone to the growth medium. Biofilm formation on surface-adsorbed furanone was unaffected or partially affected for the communication defective S. anginosus and S. intermedius mutants respectively. Adding DPD, the synthetic AI-2 communication signal, to the growth medium abolished the inhibitory effect of furanone on biofilm formation. Furthermore furanones were found to decrease bioluminescence by the AI-2 reporter strain. Taken together, these findings support the assumption that furanones interfere with microbial communication, without affecting microbial growth. Finally, we studied possible irritative and genotoxic effects of the furanones. Only after using 1000 times higher concentrations than used in the biofilm assay, did we see an irritative effect. There were no significant alterations of the genotoxic and global gene expression in mice treated with furanone. Interference with microbial communication thus may represent a novel and promising strategy to control biofilm related infections.
List of papers
|Paper I. Tore Benneche, Jessica Lönn, Anne Aamdal Scheie. 2006. Synthesis of (E)- and (Z)-5-(Bromomethylene)furan-2(5H)-one by Bromodecarboxylation of (E)-2-(5-Oxofuran-2(5H)-ylidene)acetic Acid. Synthetic communications. 36: 1401-1404. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1080/00397910500522108|
|II. Jessica Lönn-Stensrud, Fernanda C. Petersen, Tore Benneche, Anne Aamdal Scheie. 2007. Synthetic bromated furanone inhibits autoinducer-2-mediated communication and biofilm formation in oral streptococci. Oral Microbiology and Immunology. 22: 340-346. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1111/j.1399-302X.2007.00367.x|
|III. Tore Benneche, Zainab Hussain, Anne Aamdal Scheie, Jessica Lönn-Stensrud. 2008. Synthesis of 5-(bromomethylene)furan-2(5H)-ones and 3- (bromomethylene)isobenzofuran-1(3H)-ones as inhibitors of microbial quorum sensing. New J. Chem. 32: 1567-1572. Copyright The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2008. The published version of this paper is available at: https://doi.org/10.1039/b803926g|
|IV. Jessica Lönn-Stensrud, Maria A. Landin, Fernanda C. Petersen, Tore Benneche, Anne Aamdal Scheie. 2009. Furanones, potential agents for preventing Staphylococcus epidermidis biofilm infections? J. Antimicrob. Chemother. 63: 309 - 316. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1093/jac/dkn501|