Abstract
Quorum sensing (QS), which controls the survival and virulence of Pseudomonas aeruginosa, including the formation of biofilm, is considered to be a new target to overcome pathogens. The aim of this study was to identify new QS inhibitors against P. aeruginosa and provide potential treatments for clinical infections. In this study, 25 compounds were isolated from Plumula nelumbini. Among these compounds, C25 showed the most significant biofilm inhibition activity, reaching 44.63% at 100 μM without inhibiting bacterial growth. Furthermore, C25 showed significant inhibition activity of rhamnolipid, pyocyanin, and elastase. Further mechanistic studies have confirmed that C25 could downregulate key genes in the QS system, including lasI, lasR, lasA, lasB, and pqsR, and Molecular docking studies have shown that C25 can bind to the active sites of the LasR and PqsR receptors. The present study suggests that C25 is a promising QS inhibitor for treating P. aeruginosa infections.
Similar content being viewed by others
Data Availability
The datasets and referenced literature supporting the conclusions of this article are included within the article and its additional supplementary file.
Code Availability
Not applicable.
References
Lewis MT, Gales AC, Sader HS, Pfaller MA, Jones RN (2000) Frequency of occurrence and antimicrobial susceptibility patterns for pathogens isolated from Latin American patients with a diagnosis of pneumonia: results from the SENTRY antimicrobial surveillance program (1998). Diagn Microbiol Infect Dis 37(1):63–74. https://doi.org/10.1016/S0732-8893(00)00123-1
El-Mowafy SA, Abd El Galil KH, El-Messery SM, Shaaban MI (2014) Aspirin is an efficient inhibitor of quorum sensing, virulence and toxins in Pseudomonas aeruginosa. Microb Pathog 74:25–32. https://doi.org/10.1016/j.micpath.2014.07.008
Ji C, Sharma I, Pratihar D, Hudson LL, Maura D, Guney T, Rahme LG, Pesci EC, Coleman JP, Tan DS (2016) Designed small-molecule inhibitors of the anthranilyl-CoA synthetase PqsA block quinolone biosynthesis in Pseudomonas aeruginosa. ACS Chem Biol 11(11):3061–3067. https://doi.org/10.1021/acschembio.6b00575
Silby MW, Winstanley C, Godfrey SAC, Levy SB, Jackson RW (2011) Pseudomonas genomes: diverse and adaptable. FEMS Microbiol Rev 35(4):652–680. https://doi.org/10.1111/j.1574-6976.2011.00269.x
Mathee K, Narasimhan G, Valdes C, Qiu X, Matewish JM, Koehrsen M, Rokas A, Yandava CN, Engels R, Zeng E, Olavarietta R, Doud M, Smith RS, Montgomery P, White JR, Godfrey PA, Kodira C, Birren B, Galagan JE, Lory S (2008) Dynamics of Pseudomonas aeruginosa genome evolution. Proc Natl Acad Sci USA 105(8):3100. https://doi.org/10.1073/pnas.0711982105
Seleem NM, Abd El Latif HK, Shaldam MA, El-Ganiny A (2020) Drugs with new lease of life as quorum sensing inhibitors: for combating MDR Acinetobacter baumannii infections. Eur J Clin Microbiol Infect Dis 39(9):1687–1702. https://doi.org/10.1007/s10096-020-03882-z
Choi H, Ham S-Y, Cha E, Shin Y, Kim H-S, Bang JK, Son S-H, Park H-D, Byun Y (2017) Structure-activity relationships of 6- and 8-gingerol analogs as anti-biofilm agents. J Med Chem 60(23):9821–9837. https://doi.org/10.1021/acs.jmedchem.7b01426
Cao H, Krishnan G, Goumnerov B, Tsongalis J, Tompkins R, Rahme LG (2001) A quorum sensing-associated virulence gene of Pseudomonas aeruginosa encodes a LysR-like transcription regulator with a unique self-regulatory mechanism. Proc Natl Acad Sci USA 98(25):14613. https://doi.org/10.1073/pnas.251465298
Ahator SD, Zhang L (2019) Small is mighty—chemical communication systems in Pseudomonas aeruginosa. Annu Rev Microbiol 73(1):559–578. https://doi.org/10.1146/annurev-micro-020518-120044
Steenackers H, Hermans K, Vanderleyden J, De Keersmaecker SCJ (2012) Salmonella biofilms: an overview on occurrence, structure, regulation and eradication. Food Res Int 45(2):502–531. https://doi.org/10.1016/j.foodres.2011.01.038
Williams BJ, Dehnbostel J, Blackwell TS (2010) Pseudomonas aeruginosa: host defence in lung diseases. Respirology 15(7):1037–1056. https://doi.org/10.1111/j.1440-1843.2010.01819.x
Gambello MJ, Kaye S, Iglewski BH (1993) LasR of Pseudomonas aeruginosa is a transcriptional activator of the alkaline protease gene (apr) and an enhancer of exotoxin A expression. Infect Immun 61(4):1180
Shah MD, Kharkar PS, Sahu NU, Peerzada Z, Desai KB (2019) Potassium 2-methoxy-4-vinylphenolate: a novel hit exhibiting quorum-sensing inhibition in Pseudomonas aeruginosa via LasIR/RhlIR circuitry. RSC Adv 9(69):40228–40239. https://doi.org/10.1039/C9RA06612H
Lee J, Wu J, Deng Y, Wang J, Wang C, Wang J, Chang C, Dong Y, Williams P, Zhang L-H (2013) A cell-cell communication signal integrates quorum sensing and stress response. Nat Chem Biol 9(5):339–343. https://doi.org/10.1038/nchembio.1225
Ng W-L, Bassler BL (2009) Bacterial quorum-sensing network architectures. Annu Rev Genet 43(1):197–222. https://doi.org/10.1146/annurev-genet-102108-134304
Xu Y, Tong X, Sun P, Bi L, Lin K (2017) Virtual screening and biological evaluation of biofilm inhibitors on dual targets in quorum sensing system. Fut Med Chem 9(17):1983–1994. https://doi.org/10.4155/fmc-2017-0127
Ledgham F, Ventre I, Soscia C, Foglino M, Sturgis JN, Lazdunski A (2003) Interactions of the quorum sensing regulator QscR: interaction with itself and the other regulators of Pseudomonas aeruginosa LasR and RhlR. Mol Microbiol 48(1):199–210. https://doi.org/10.1046/j.1365-2958.2003.03423.x
Defoirdt T (2018) Quorum-sensing systems as targets for antivirulence therapy. Trends Microbiol 26(4):313–328. https://doi.org/10.1016/j.tim.2017.10.005
Kostylev M, Kim DY, Smalley NE, Salukhe I, Greenberg EP, Dandekar AA (2019) Evolution of the Pseudomonas aeruginosa quorum-sensing hierarchy. Proc Natl Acad Sci USA 116(14):7027. https://doi.org/10.1073/pnas.1819796116
Kumar L, Chhibber S, Harjai K (2013) Zingerone inhibit biofilm formation and improve antibiofilm efficacy of ciprofloxacin against Pseudomonas aeruginosa PAO1. Fitoterapia 90:73–78. https://doi.org/10.1016/j.fitote.2013.06.017
Deng J, Chen S, Yin X, Wang K, Liu Y, Li S, Yang P (2013) Systematic qualitative and quantitative assessment of anthocyanins, flavones and flavonols in the petals of 108 lotus (Nelumbo nucifera) cultivars. Food Chem 139(1):307–312. https://doi.org/10.1016/j.foodchem.2013.02.010
Fang Y, Li Q, Shao Q, Wang B, Wei Y (2017) A general ionic liquid pH-zone-refining countercurrent chromatography method for separation of alkaloids from Nelumbo nucifera Gaertn. J Chromatogr A 1507:63–71. https://doi.org/10.1016/j.chroma.2017.05.048
Tian W, Zhi H, Yang C, Wang L, Long J, Xiao L, Liang J, Huang Y, Zheng X, Zhao S, Zhang K, Zheng J (2018) Chemical composition of alkaloids of Plumula nelumbinis and their antioxidant activity from different habitats in China. Ind Crops Prod 125:537–548. https://doi.org/10.1016/j.indcrop.2018.09.045
Bao L, Guo J, Feng L, Zhou X, Lu Q (2019) Efficacy of artesunate against Pseudomonas aeruginosa biofilm mediated by iron. Biomed Res Int 2019:4810217. https://doi.org/10.1155/2019/4810217
Fong J, Yuan M, Jakobsen TH, Mortensen KT, Delos Santos MMS, Chua SL, Yang L, Tan CH, Nielsen TE, Givskov M (2017) Disulfide bond-containing ajoene analogues as novel quorum sensing inhibitors of Pseudomonas aeruginosa. J Med Chem 60(1):215–227. https://doi.org/10.1021/acs.jmedchem.6b01025
Liu J, Hou J-S, Li Y-B, Miao Z-Y, Sun P-H, Lin J, Chen W-M (2020) Novel 2-substituted 3-hydroxy-1,6-dimethylpyridin-4(1H)-ones as dual-acting biofilm inhibitors of Pseudomonas aeruginosa. J Med Chem 63(19):10921–10945. https://doi.org/10.1021/acs.jmedchem.0c00763
Nalca Y, Jänsch L, Bredenbruch F, Geffers R, Buer J, Häussler S (2006) Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PAO1: a global approach. Antimicrob Agents Chemother 50(5):1680. https://doi.org/10.1128/AAC.50.5.1680-1688.2006
Liu Y, Jiang Y, Zhu J, Huang J, Zhang H (2019) Inhibition of bacterial adhesion and biofilm formation of sulfonated chitosan against Pseudomonas aeruginosa. Carbohydr Polym 206:412–419. https://doi.org/10.1016/j.carbpol.2018.11.015
Tan SY-Y, Chua S-L, Chen Y, Rice SA, Kjelleberg S, Nielsen TE, Yang L, Givskov M (2013) Identification of five structurally unrelated quorum-sensing inhibitors of Pseudomonas aeruginosa from a natural-derivative database. Antimicrob Agents Chemother 57(11):5629. https://doi.org/10.1128/AAC.00955-13
Essar DW, Eberly L, Hadero A, Crawford IP (1990) Identification and characterization of genes for a second anthranilate synthase in Pseudomonas aeruginosa: interchangeability of the two anthranilate synthases and evolutionary implications. J Bacteriol 172(2):884–900. https://doi.org/10.1128/jb.172.2.884-900.1990
Li S, Zhang Y, Jiang K, Wang H, Lin F (2021) Inhibitory effects of novel 1,4-disubstituted 1,2,3-triazole compounds on quorum-sensing of P. aeruginosa PAO1. Eur J Clin Microbiol Infect Dis 40(2):373–379. https://doi.org/10.1007/s10096-020-03998-2
Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4):611–622. https://doi.org/10.1373/clinchem.2008.112797
Davies DG, Parsek MR, Pearson JP, Iglewski BH, Costerton JW, Greenberg EP (1998) The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science 280(5361):295. https://doi.org/10.1126/science.280.5361.295
Charlton TS, De Nys R, Netting A, Kumar N, Hentzer M, Givskov M, Kjelleberg S (2000) A novel and sensitive method for the quantification of N-3-oxoacyl homoserine lactones using gas chromatography–mass spectrometry: application to a model bacterial biofilm. Environ Microbiol 2(5):530–541. https://doi.org/10.1046/j.1462-2920.2000.00136.x
Hentzer M, Riedel K, Rasmussen TB, Heydorn A, Andersen JB, Parsek MR, Rice SA, Eberl L, Molin S, Høiby N, Kjelleberg S, Givskov M (2002) Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology 148(1):87–102. https://doi.org/10.1099/00221287-148-1-87
Grande R, Puca V, Muraro R (2020) Antibiotic resistance and bacterial biofilm. Expert Opin Ther Pat 30(12):897–900. https://doi.org/10.1080/13543776.2020.1830060
Topa SH, Palombo EA, Kingshott P, Blackall LL (2020) Activity of cinnamaldehyde on quorum sensing and biofilm susceptibility to Antibiotics in Pseudomonas aeruginosa. Microorganisms. https://doi.org/10.3390/microorganisms8030455
Song Y, Cai Z-H, Lao Y-M, Jin H, Ying K-Z, Lin G-H, Zhou J (2018) Antibiofilm activity substances derived from coral symbiotic bacterial extract inhibit biofouling by the model strain Pseudomonas aeruginosa PAO1. Microb Biotechnol 11(6):1090–1105. https://doi.org/10.1111/1751-7915.13312
Hegazy WAH, Khayat MT, Ibrahim TS, Nassar MS, Bakhrebah MA, Abdulaal WH, Alhakamy NA, Bendary MM (2020) Repurposing anti-diabetic drugs to cripple quorum sensing in Pseudomonas aeruginosa. Microorganisms. https://doi.org/10.3390/microorganisms8091285
Acknowledgements
This work was supported by the research grant from the National Natural Science Foundation of China (No. 81773593, 81872759, 82073977, 81803378). We sincerely thank Dr. Liang Yang from the Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University for gifting the PAO1-gfp, PAO1-lasB-gfp, PAO1-rhlA-gfp, PAO1-pqsA-gfp strain.
Author information
Authors and Affiliations
Contributions
Conceptualization: HC, LW and JZ; Methodology: YS, LW, ZX, ZH, and JF; Formal analysis and investigation: HH, WW, ZG; Writing, original draft preparation: HC; Writing, review and editing: PS and JZ; Funding acquisition: PS and JZ. All the authors approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Approval
No ethical approval was required for this study.
Informed consent
All authors agreed on the submitted version.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Chen, H., Wu, L., Su, Y. et al. Inhibitory Effects of Compounds from Plumula nelumbinis on Biofilm and Quorum Sensing Against P. aeruginosa. Curr Microbiol 79, 236 (2022). https://doi.org/10.1007/s00284-022-02914-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00284-022-02914-5