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Synthetic furanones and inhibition of biofilm formation

Lönn-Stensrud, Jessica
Doctoral thesis
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dravhandling-lonn-stensrud.pdf (618.3Kb)
Year
2009
Permanent link
http://urn.nb.no/URN:NBN:no-44600

CRIStin
1144883

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Appears in the following Collection
  • Det odontologiske fakultet [1010]
  • CRIStin høstingsarkiv [15167]
Abstract
In 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.
 
I denna studien har vi undersökt om furanoner kan förhindra bildandet av biofilmer. Vår första målsättning var att finna en ny syntesväg för (Z)-5-bromomethylene-2(5H)-furanone, en furanon som produceras naturligt av makro-algen Delisa pulchra, samt att undersöka dess effekt på biofilmer av Streptococcus anginosus, Streptococcus intermedius och Streptococcus mutans. Vi syntetiserade även 5-(bromomethylene)furan-2(5H)-ones och 3- (bromomethylene)isobenzofuran-1(3H)-ones för att vidare kunna undersöka deras effekt på biofilm av Staphylococcus epidermidis. Effekten på biofilm blev undersökt genom att tillsätta furanoner till växtmediet eller genom att observera hur biofilm bildas på en ytadsorberad furanon. Furanonerna minskade effektivt bildandet av biofilm i båda applikationsmetoderna, men ytadsorberad furanon var mest effektiv. Koncentrationerna av furanon som användes hade ingen effekt på bakteriell tillväxt och koncentrationerna låg också långt under de fastställda MIC (Minimal Inhibitory Concentration)-värdena, vilket indikerade att effekten inte var ett resultat av en antimikrobiell effekt. För att kunna bestämma om den inhibitoriska effekten var associerad med furanonernas förmåga att påverka mikrobiell AI-2 kommunikation, inkluderades en mutant som saknar förmåga att kommunicera genom AI-2. Till skillnad från motsvarande vildtyp var mängden biofilm bildad av S. anginosus and S. intermedius mutanterna, som saknar förmåga att kommunicera genom AI-2, inte påverkad av furanoner tillsatta till växtmediet. Mängd bildad biofilm av S. anginosus and S. intermedius mutanterna på ytadsorberad furanon var oförändrad eller endast delvis påverkad hos de respektive mutanterna. Genom att tillsätta DPD, den syntetiska AI-2 kommunikationssignalen, till växtmediet kunde den inhibitoriska effekten av furanon upphävas. Vidare fann vi att furanon minskade bioluminescence hos AI-2 reporter-stammen. Tillsammans understöder resultaten antagandet att furanoner påverkar mikrobiell kommunikation utan att påverka mikrobiell tillväxt.

Slutligen undersökte vi möjliga skadliga och genotoxiska effekter av furanoner. Först efter att ha använt 1000 gånger högre koncentrationer än de vi använde i biofilm-försöken såg vi en skadlig effekt. Vi såg inga signifikanta förändringar i våra genotoxiska tester hos möss som blivit behandlade med furanon.

Möjligheten att kunna påverka bakteriell kommunikation kan därför representera en ny och lovande strategi för att kunna kontrollera bakteriella biofilmrelaterade infektioner.
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
 
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