Evaluation of Potential Genotoxicity of New Furanone Derivatives – QS Inhibitors

E.V. Babynin*, R.M. Glazkova, A.R. Kurbangalieva**

Kazan Federal University, Kazan, 420008 Russia

E-mail: *edward.babynin@kpfu.ru, **Almira.Kurbangalieva@kpfu.ru

Received January 30, 2017

Full text PDF

Abstract

Quorum sensing (QS) is a regulatory mechanism by which bacteria coordinate the expression of certain genes in response to their population density by producing, releasing and detecting small signal molecules. The discovery that QS regulates bacterial virulence and biofilm formation opens up new ways to control certain bacterial infections. The recent studies reported that synthetic halogenated furanones are capable of inhibiting bacterial QS and exhibited favorable therapeutic effects. New halogenated furanone derivatives have been tested for their ability to inhibit QS system. Three compounds having QS inhibitory activity have been identified among the synthesized compounds. The selected compounds have been also tested for the presence of genotoxicity using the Ames test and SOS-lux test. None of the compounds have shown any mutagenic activity in the bacterial test systems.

Keywords: 2(5Н)-furanones, unsaturated γ-lactones, quorum sensing, genotoxicity, Salmonella

Acknowledgments. The study was supported by the Russian Science Foundation (project no. 15-14-00046).

Figure Captions

Fig. 1. The structure of certain furanone derivatives tested in this study: F1 – 3,4-dichloro-5-hydroxy-2(5Н)-furanone, mucochloric acid; F5 – 3,4-dichloro-5-isopropoxy-2(5Н)-furanone; F7 – 5-(2-bromoethoxy)-3,4-dichloro-2(5Н)-furanone; F9 – 5-n-butoxy-3,4-dichloro-2(5Н)- furanone; F17 – 3-chloro-5-hydroxy-4-[(4-ethylphenyl)sulfanyl]-2(5Н)-furanone.

Fig. 2. The influence of furanone F1 at various concentrations on spontaneous bioluminescence of MG1655/pVFR1 strain.

Fig. 3. The influence of various furanone derivatives on AHL-induced bioluminescence of MG1655/pVFR1 strain (NC – negative control, PC – positive control).

Fig. 4. The influence of furanones F5 and F9 on the number of His+ revertants of mutations in ТА1535 and ТА1538 Salmonella typhimurium in the Ames test (C – control).

Fig. 5. The influence of furanone F7 on the number of His+ revertants of mutations in ТА1535 and ТА1538 Salmonella typhimurium in the Ames test (C – control, PC – positive control).

Fig. 6. The bioluminescence intensity of ТА1535/pDEW238 Salmonella typhimurium at various concentrations of furanones F5, F7, and F9.

References

  1. Fux C.A., Costerton J.W., Stewart P.S., Stoodley P. Survival strategies of infectious biofilms. Trends Microbiol., 2005, vol. 13, no. 1, pp. 34–40. doi: 10.1016/j.tim.2004.11.010
  2. LaSarre B., Federle M.J. Exploiting quorum sensing to confuse bacterial pathogens. Microbiol. Mol. Biol. Rev., 2013, vol. 77, no. 1, pp. 73–111. doi: 10.1128/MMBR.00046-12.
  3. Castillo-Juárez I., Maeda T., Mandujano-Tinoco E.A., Tomas M., Párez-Eretza B., Garcia-Contreras S.J., Wood T.K., García-Contreras R. Role of quorum sensing in bacterial infections. World J. Clin. Cases, 2015, vol. 3, no. 7, pp. 575–598. doi: 10.12998/wjcc.v3.i7.575.
  4. Reuter K., Steinbach A., Helms V. Interfering with bacterial quorum sensing. Perspect. Med. Chem., 2016, vol. 8, pp. 1–15. doi: 10.4137/PMC.S13209.
  5. Guo M., Gamby S., Zheng Y., Sintim H.O. Small molecule inhibitors of AI-2 signaling in bacteria: State-of-the-art and future perspectives for anti-quorum sensing agents. Int. J. Mol. Sci., 2013, vol. 14, no. 9, pp. 17694–17728. doi: 10.3390/ijms140917694.
  6. Taga M.E., Bassler B.L. Chemical communication among bacteria. Proc. Natl. Acad. Sci. U. S. A., 2003, vol. 100, suppl. 2, pp. 14549–14554. doi: 10.1073 pnas.1934514100.
  7. Federle M.J., Bassler B.L. Interspecies communication in bacteria. J. Clin. Invest., 2003, vol. 112, no. 9, pp. 1291–1299. doi: 10.1172/JCI200320195.
  8. Schauder S., Bassler B.L. The languages of bacteria. Genes Dev., 2001, vol. 15, no. 12, pp. 1468–1480. doi: 10.1101/gad.899601.
  9. Hentzer M., Givskov M. Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections. J. Clin. Invest., 2003, vol. 112, no. 9, pp. 1300–1307. doi: 10.1172/JCI20074.
  10. Rasmussen T.B., Givskov M. Quorum-sensing inhibitors as anti-pathogenic drugs. Int. J. Med. Microbiol., 2006, vol. 296, nos. 2–3, pp. 149–161. doi: 10.1016/j.ijmm.2006.02.005.
  11. Manefield M., Rasmussen T.B., Henzter M., Andersen J.B., Steinberg P., Kjelleberg S., Givskov M. Halogenated furanones inhibit quorum sensing through accelerated LuxR turnover. Microbiology, 2002, vol. 148, pt. 4, pp. 1119–1127. doi: 10.1099/00221287-148-4-1119.
  12. Ren D., Sims J.J., Wood T.K. Inhibition of biofilm formation and swarming of Escherichia coli by (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone. Environ. Microbiol., 2001, vol. 3, no. 11, pp. 731–736. doi: 10.1046/j.1462-2920.2001.00249.x.
  13. Ren D., Sims J.J., Wood T.K. Inhibition of biofilm formation and swarming of Bacillus subtilis by (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone. Lett. Appl. Microbiol., 2002, vol. 34, no. 4, pp. 293–299. doi: 10.1046/j.1472-765x.2002.01087.x.
  14. Surette M.G., Bassler B.L. Quorum sensing in Escherichia coli and Salmonella typhimurium. Proc. Natl. Acad. Sci. U. S. A., 1998, vol. 95, no. 12, pp. 7046–7050.
  15. Maron D., Ames B.N. Revised methods for the Salmonella mutagenicity test. Mutat. Res., 1983, vol. 113, nos. 3–4, pp. 173–215. doi: 10.1016/0165-1161(83)90010-9.
  16. Davidov Y., Rozen R., Smulski D.R., Van Dyk T.K., Vollmer A.C., Elsemore D.A., LaRossa R.A., Belkin S. Improved bacterial SOS promoter::lux fusions for genotoxicity detection. Mutat. Res., 2000, vol. 466, no. 1, pp. 97–107. doi: 10.1016/S1383-5718(99)00233-8.
  17. Quillardet P., Huisman O., Dari R., Hofnung M. SOS Chromotest, a direct assay of induction of an SOS function in Escherichia coli K-12 to measure genotoxicity. Proc. Natl. Acad. Sci. U. S. A., 1982, vol. 79, no. 19, pp. 5971–5975.
  18. Oda Y., Nakamura S., Oki L., Kato T., Shinagawa H. Evaluation of the new system (umu-test) for the detection of environmental mutagens and carcinogens. Mutat. Res., 1985, vol. 147, no. 5, pp. 219–229. doi: 10.1016/0165-1161(85)90062-7.

For citation: Babynin E.V., Glazkova R.M., Kurbangalieva A.R. Evaluation of potential genotoxicity of new furanone derivatives – QS inhibitors. Uchenye Zapiski Kazanskogo Universiteta. Seriya Estestvennye Nauki, 2017, vol. 159, no. 2, pp. 283–292. (In Russian)


The content is available under the license Creative Commons Attribution 4.0 License.