Characterization of natural product inhibitors of quorum sensing in Pseudomonas aeruginosa reveals competitive inhibition of RhlR by ortho -vanillin.
| العنوان: | Characterization of natural product inhibitors of quorum sensing in Pseudomonas aeruginosa reveals competitive inhibition of RhlR by ortho -vanillin. |
|---|---|
| المؤلفون: | Woods KE; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Akhter S; Center for Computational Biology, University of Kansas, Lawrence, KS 66045., Rodriguez B; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Townsend KA; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Smith N; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Smith B; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Wambua A; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Craddock V; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Abisado-Duque RG; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Santa EE; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706., Manson DE; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706., Oakley BR; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Hancock LE; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Miao Y; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045.; Center for Computational Biology, University of Kansas, Lawrence, KS 66045.; Current location: Department of Pharmacology and Computational Medicine Program, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599., Blackwell HE; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706., Chandler JR; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 13. Date of Electronic Publication: 2024 Mar 13. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Quorum sensing (QS) is a cell-cell signaling system that enables bacteria to coordinate population density-dependent changes in behavior. This chemical communication pathway is mediated by diffusible N -acyl L-homoserine lactone signals and cytoplasmic signal-responsive LuxR-type receptors in Gram-negative bacteria. As many common pathogenic bacteria use QS to regulate virulence, there is significant interest in disrupting QS as a potential therapeutic strategy. Prior studies have implicated the natural products salicylic acid, cinnamaldehyde and other related benzaldehyde derivatives as inhibitors of QS in the opportunistic pathogen Pseudomonas aeruginosa , yet we lack an understanding of the mechanisms by which these compounds function. Herein, we evaluate the activity of a set of benzaldehyde derivatives using heterologous reporters of the P. aeruginosa LasR and RhlR QS signal receptors. We find that most tested benzaldehyde derivatives can antagonize LasR or RhlR reporter activation at micromolar concentrations, although certain molecules also caused mild growth defects and nonspecific reporter antagonism. Notably, several compounds showed promising RhlR or LasR specific inhibitory activities over a range of concentrations below that causing toxicity. Ortho- Vanillin, a previously untested compound, was the most promising within this set. Competition experiments against the native ligands for LasR and RhlR revealed that ortho -vanillin can interact competitively with RhlR but not with LasR. Overall, these studies expand our understanding of benzaldehyde activities in the LasR and RhlR receptors and reveal potentially promising effects of ortho -vanillin as a small molecule QS modulator against RhlR. |
| References: | Appl Microbiol Biotechnol. 2019 Apr;103(8):3521-3535. (PMID: 30852658) Mol Gen Genet. 1985;198(2):348-52. (PMID: 3920478) Mol Cell. 2011 Apr 22;42(2):199-209. (PMID: 21504831) J Biol Chem. 2017 Mar 10;292(10):4064-4076. (PMID: 28119451) Chem Rev. 2011 Jan 12;111(1):1-3. (PMID: 21222491) mBio. 2018 May 22;9(3):. (PMID: 29789364) J Am Chem Soc. 2015 Nov 25;137(46):14626-39. (PMID: 26491787) ACS Chem Biol. 2018 Sep 21;13(9):2655-2662. (PMID: 30114353) J Bacteriol. 2003 Apr;185(7):2080-95. (PMID: 12644477) Nat Protoc. 2006;1(1):153-61. (PMID: 17406227) Chem Rev. 2011 Jan 12;111(1):195-208. (PMID: 21087050) Cell. 1999 Jan 8;96(1):47-56. (PMID: 9989496) Infect Immun. 2005 Sep;73(9):5319-28. (PMID: 16113247) Antimicrob Agents Chemother. 2009 Jun;53(6):2432-43. (PMID: 19364871) J Bacteriol. 1994 Jan;176(2):269-75. (PMID: 8288518) Antimicrob Agents Chemother. 2006 Nov;50(11):3674-9. (PMID: 16966394) ACS Infect Dis. 2020 Apr 10;6(4):649-661. (PMID: 32037806) Structure. 2022 Dec 1;30(12):1626-1636.e4. (PMID: 36379213) J Clin Invest. 2003 Nov;112(9):1288-90. (PMID: 14597752) Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13815-20. (PMID: 23924613) Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):245-254. (PMID: 30559209) Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2408-13. (PMID: 10051655) Nat Rev Microbiol. 2016 Aug 11;14(9):576-88. (PMID: 27510864) Infect Immun. 1996 Jan;64(1):37-43. (PMID: 8557368) J Burn Care Rehabil. 1999 Jan-Feb;20(1 Pt 1):42-9. (PMID: 9934636) Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):715-20. (PMID: 9892699) J Am Chem Soc. 2012 May 16;134(19):8212-21. (PMID: 22510154) J Bacteriol. 1996 Oct;178(20):5995-6000. (PMID: 8830697) Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17981-6. (PMID: 24143808) J Bacteriol. 1997 Sep;179(18):5756-67. (PMID: 9294432) Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2752-7. (PMID: 11226312) Chem Biol. 2014 Oct 23;21(10):1361-1369. (PMID: 25242287) Antimicrob Agents Chemother. 2013 Nov;57(11):5629-41. (PMID: 24002091) Org Biomol Chem. 2015 Feb 7;13(5):1453-62. (PMID: 25474181) ACS Infect Dis. 2016 Jan 8;2(1):32-38. (PMID: 26807436) FEMS Microbiol Rev. 2016 Sep;40(5):774-94. (PMID: 27268906) Mol Cell. 2009 Jul 31;35(2):143-53. (PMID: 19647512) FEMS Microbiol Lett. 1997 Nov 15;156(2):193-8. (PMID: 9513264) Microbiology (Reading). 2002 Apr;148(Pt 4):1119-1127. (PMID: 11932456) Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):197-201. (PMID: 8278364) J Bacteriol. 1996 Nov;178(22):6618-22. (PMID: 8932319) Drug Dev Res. 2023 Feb;84(1):45-61. (PMID: 36419404) Mol Microbiol. 2006 Jan;59(2):602-9. (PMID: 16390453) J Bacteriol. 2013 Jul;195(14):3125-34. (PMID: 23645601) PLoS One. 2017 Apr 28;12(4):e0176883. (PMID: 28453568) J Bacteriol. 2003 Apr;185(7):2066-79. (PMID: 12644476) Chembiochem. 2014 Feb 10;15(3):435-42. (PMID: 24478193) Nat Prod Res. 2022 Mar;36(6):1610-1615. (PMID: 33615940) |
| معلومات مُعتمدة: | P20 GM103418 United States GM NIGMS NIH HHS; R35 GM131817 United States GM NIGMS NIH HHS; R35 GM133572 United States GM NIGMS NIH HHS; T34 GM136453 United States GM NIGMS NIH HHS |
| تواريخ الأحداث: | Date Created: 20240401 Latest Revision: 20240405 |
| رمز التحديث: | 20240405 |
| مُعرف محوري في PubMed: | PMC10979890 |
| DOI: | 10.1101/2024.02.24.581676 |
| PMID: | 38559250 |
| قاعدة البيانات: | MEDLINE |
كن أول من يترك تعليقا!