Skip to main content

Advertisement

SpringerLink
Log in

The effectiveness of anti-biofilm and anti-virulence properties of dihydrocelastrol and dihydrocelastryl diacetate in fighting against methicillin-resistant Staphylococcus aureus

  • Original Paper
  • Published:
Archives of Microbiology Aims and scope Submit manuscript

Abstract

Human pathogens have readily been converted into multidrug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), because of the long-term use of conventional antibiotics. In addition, the biofilms formed by S. aureus cells are especially problematic and are related to the persistence of chronic infections because they constitute a major mechanism of promoting tolerance to diverse antimicrobial agents. Hence, the inhibitions of biofilm formation and/or toxin production are accepted as alternative means of controlling S. aureus infections. The present study was aimed at identifying novel anti-biofilm and/or anti-virulence compounds in friedelane-based pentacyclic triterpenoids present in many edible and medicinal plants—and investigating them against MRSA strains. As a result, dihydrocelastrol and dihydrocelastryl diacetate were found to both inhibit the biofilm formation of, and to disrupt the preformed biofilms of, MRSA strains to an increasingly greater degree with increasing concentrations of each compound. Furthermore, these two triterpenoids also clearly inhibited the hemolytic activity of MRSA—and in-line with their anti-biofilm activities, rendered the cell more hydrophilic. Additionally, corroborating phenotypic results, transcriptional analyses showed that both dihydrocelastrol and dihydrocelastryl diacetate disturbed the expression of gene related to α-hemolysin (hla) and down-regulated the expressions of the crucial biofilm-associated genes (agrA, sarA, ica, RNAIII, and rbf) in MRSA. The findings of this study suggest that friedelane-based pentacyclic triterpenoids—especially dihydrocelastrol and dihydrocelastryl diacetate—have the potential to be candidates both for use in controlling biofilm-related infections and for use as important components of anti-virulence strategies for fighting against MRSA infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • An YH, Friedman RJ (1998) Concise review of mechanisms of bacterial adhesion to biomaterial surfaces. J Biomed Mater Res 43(3):338–348

    Article  CAS  PubMed  Google Scholar 

  • Arciola CR, Campoccia D, Speziale P, Montanaro L, Costerton JW (2012) Biofilm formation in Staphylococcus implant infections. A review of molecular mechanisms and implications for biofilm-resistant materials. Biomaterials 33(26):5967–5982

    Article  CAS  PubMed  Google Scholar 

  • Beenken KE, Dunman PM, McAleese F, Macapagal D, Murphy E, Projan SJ, Blevins JS, Smeltzer MS (2004) Global Gene Expression in Staphylococcus aureus Biofilms. J Bacteriol 186(14):4665–4684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beenken KE, Mrak LN, Griffin LM, Zielinska AK, Shaw LN, Rice KC, Horswill AR, Bayles KW, Smeltzer MS (2010) Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation. PLoS One 5(5):e10790

    Article  PubMed  PubMed Central  Google Scholar 

  • Boles BR, Horswill AR (2011) Staphylococcal biofilm disassembly. Trends Microbiol 19(9):449–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bubeck Wardenburg J, Bae T, Otto M, Deleo FR, Schneewind O (2007) Poring over pores: α-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med 13(12):1405–1406

    Article  PubMed  Google Scholar 

  • Caiazza NC, O’Toole GA (2003) Alpha-toxin is required for biofilm formation by Staphylococcus aureus. J Bacteriol 185(10):3214–3217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Liu T, Wang K, Hou C, Cai S, Huang Y, Du Z, Huang H, Kong J, Chen Y (2016) Baicalein inhibits Staphylococcus aureus biofilm formation and the quorum sensing system in vitro. PLoS One 11(4):e0153468

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheung AL, Ying P (1994) Regulation of α- and β-hemolysins by the sar locus of Staphylococcus aureus. J Bacteriol 176(3):580–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung AL, Koomey JM, Butler CA, Projan SJ, Fischetti VA (1992) Regulation of exoprotein expression in Staphylococcus aureus by a locus (sar) distinct from agr. Proc Natl Acad Sci USA 89(14):6462–6466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christensen GD, Simpson WA, Younger JJ, Baddour LM, Barrett FF, Melton DM, Beachey EH (1985) Adherence of coagulase-negative staphylococci to plastic tissue culture plates: a quantitative model for the adherence of staphylococci to medical devices. J Clin Microbiol 22(6):996–1006

    CAS  PubMed  PubMed Central  Google Scholar 

  • Clinical and Laboratory Standards Institute (2007) Performance standards for antimicrobial susceptibility testing; 17th informational supplement, M100-S17. Clinical and Laboratory Standards Institute, Wayne

    Google Scholar 

  • Costerton JW, Stewart PS, Greenberg EP (1999) Bacterial biofilms: a common cause of persistent infections. Science 284(5418):1318–1322

    Article  CAS  PubMed  Google Scholar 

  • Cramton SE, Gerke C, Schnell NF, Nichols WW, Götz F (1999) The intercellular adhesion (ica) locus is present in Staphylococcus aureus and is required for biofilm formation. Infect Immun 67(10):5427–5433

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deora R, Tseng T, Misra TK (1997) Alternative transcription factor σSB of Staphylococcus aureus: characterization and role in transcription of the global regulatory locus sar. J Bacteriol 179(20):6355–6359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dinges MM, Orwin PM, Schlievert PM (2000) Exotoxins of Staphylococcus aureus. Clin Microbiol Rev 13(1):16–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donlan RM, Costerton JW (2002) Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15(2):167–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunne WM Jr (2002) Bacterial adhesion: seen any good biofilms lately? Clin Microbiol Rev 15(2):155–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Field D, O’Connor R, Cotter PD, Ross RP, Hill C (2016) In vitro activities of nisin and nisin derivatives alone and in combination with antibiotics against Staphylococcus biofilms. Front Microbiol 7:508

    PubMed  PubMed Central  Google Scholar 

  • Fitzpatrick F, Humphreys H, O’Gara JP (2005) Evidence for icaADBC-independent biofilm development mechanism in methicillin-resistant Staphylococcus aureus clinical isolates. J Clin Microbiol 43(4):1973–1976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gil C, Solano C, Burgui S, Latasa C, Garcia B, Toledo-Arana A, Lasa I, Valle J (2014) Biofilm matrix exoproteins induce a protective immune response against Staphylococcus aureus biofilm infection. Infect Immun 82(3):1017–1029

    Article  PubMed  PubMed Central  Google Scholar 

  • Gilabert M, Marcinkevicius K, Andujar S, Schiavone M, Arena ME, Bardón A (2015) Sesqui- and triterpenoids from the liverwort Lepidozia chordulifera inhibitors of bacterial biofilm and elastase activity of human pathogenic bacteria. Phytomedicine 22(1):77–85

    Article  CAS  PubMed  Google Scholar 

  • Gustafsson E, Nilsson P, Karlsson S, Arvidson S (2004) Characterizing the dynamics of the quorum-sensing system in Staphylococcus aureus. J Mol Microbiol Biotechnol 8(4):232–242

    Article  PubMed  Google Scholar 

  • Hentzer M, Givskov M (2003) Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections. J Clin Invest 112(9):1300–1307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffman LR, D’Argenio DA, MacCoss MJ, Zhang Z, Jones RA, Miller SI (2005) Aminoglycoside antibiotics induce bacterial biofilm formation. Nature 436(7054):1171–1175

    Article  CAS  PubMed  Google Scholar 

  • Høiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O (2010) Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 35(4):322–332

    Article  PubMed  Google Scholar 

  • Jusko M, Potempa J, Kantyka T, Bielecka E, Miller HK, Kalinska M, Dubin G, Garred P, Shaw LN, Blom AM (2014) Staphylococcal proteases aid in evasion of the human complement system. J Innate Immun 6(1):31–46

    Article  CAS  PubMed  Google Scholar 

  • Kiran MD, Adikesavan NV, Cirioni O, Giacometti A, Silvestri C, Scalise G, Ghiselli R, Saba V, Orlando F, Shoham M, Balaban N (2008) Discovery of a quorum sensing inhibitor of drug-resistant staphylococcal infections by structure-based virtual screening. Mol Pharmacol 73(5):1578–1586

    Article  CAS  PubMed  Google Scholar 

  • Kleerebezem M, Quadri LE, Kuipers OP, de Vos WM (1997) Quorum sensing by peptide pheromones and two-component signal-transduction systems in Gram-positive bacteria. Mol Microbiol 24(5):895–904

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Kim YG, Yong Ryu S, Lee J (2016) Calcium-chelating alizarin and other anthraquinones inhibit biofilm formation and the hemolytic activity of Staphylococcus aureus. Sci Rep 6:19267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li JW, Vederas JC (2009) Drug discovery and natural products: end of an era or an endless frontier? Science 325(5937):161–165

    Article  PubMed  Google Scholar 

  • Lowy FD (1998) Staphylococcus aureus infections. N Engl J Med 339(8):520–532

    Article  CAS  PubMed  Google Scholar 

  • Luong TT, Lei MG, Lee CY (2009) Staphylococcus aureus Rbf activates biofilm formation in vitro and promotes virulence in a murine foreign body infection model. Infect Immun 77(1):335–340

    Article  CAS  PubMed  Google Scholar 

  • Manna AC, Bayer MG, Cheung AL (1998) Transcriptional analysis of different promoters in the sar locus in Staphylococcus aureus. J Bacteriol 180(15):3828–3836

    CAS  PubMed  PubMed Central  Google Scholar 

  • McAdow M, DeDent AC, Emolo C, Cheng AG, Kreiswirth BN, Missiakas DM, Schneewind O (2012) Coagulases as determinants of protective immune responses against Staphylococcus aureus. Infect immune 80(10):3389–3398

    Article  CAS  Google Scholar 

  • Nosyk O, ter Haseborg E, Metzger U, Frimmel FH (2008) A standardized pre-treatment method of biofilm flocs for fluorescence microscopic characterization. J Microbiol Methods 75(3):449–456

    Article  CAS  PubMed  Google Scholar 

  • Ohlsen K, Koller KP, Hacker J (1997) Analysis of expression of the alpha-toxin gene (hla) of Staphylococcus aureus by using a chromosomally encoded hla:lacZ gene fusion. Infect Immun 65(9):3606–3614

    CAS  PubMed  PubMed Central  Google Scholar 

  • Oscarsson J, Kanth A, Tegmark-Wisell K, Arvidson S (2006) SarA is a repressor of hla (α-hemolysin) transcription in Staphylococcus aureus: its apparent role as an activator of hla in the prototype strain NCTC 8325 depends on reduced expression of sarS. J Bacteriol 188(24):8526–8533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otto M (2013) Staphylococcal infections: mechanisms of biofilm maturation and detachment as critical determinants of pathogenicity. Annu Rev Med 64:175–188

    Article  CAS  PubMed  Google Scholar 

  • Parsek MR, Greenberg EP (2005) Sociomicrobiology: the connections between quorum sensing and biofilms. Trends Microbiol 13(1):27–33

    Article  CAS  PubMed  Google Scholar 

  • Periasamy S, Joo HS, Duong AC, Bach TH, Tan VY, Chatterjee SS, Otto M (2012) How Staphylococcus aureus biofilms develop their characteristic structure. Proc Natl Acad Sci USA 109(4):1281–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Potera C (1999) Forging a link between biofilms and disease. Science 283(5409):1837–1839

    Article  CAS  PubMed  Google Scholar 

  • Schmidt BM, Ribnicky DM, Lipsky PE, Raskin I (2007) Revisiting the ancient concept of botanical therapeutics. Nat Chem Boil 3(7):360–366

    Article  CAS  Google Scholar 

  • Singh R, Ray P, Das A, Sharma M (2010) Penetration of antibiotics through Staphylococcus aureus and Staphylococcus epidermidis biofilms. J Antimicrob Chemother 65(9):1955–1958

    Article  CAS  PubMed  Google Scholar 

  • Song L, Hobaugh MR, Shustak C, Cheley S, Bayley H, Gouaux JE (1996) Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore. Science 274(5294):1859–1866

    Article  CAS  PubMed  Google Scholar 

  • Sperandio V (2007) Novel approaches to bacterial infection therapy by interfering with bacteria-to-bacteria signaling. Expert Rev Anti Infect Ther 5(2):271–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stefani S, Varaldo PE (2003) Epidemiology of methicillin-resistant staphylococci in Europe. Clin Microbiol Infect 9(12):1179–1186

    Article  CAS  PubMed  Google Scholar 

  • Ta CA, Arnason JT (2015) Mini review of phytochemicals and plant taxa with activity as microbial biofilm and quorum sensing inhibitors. Molecules 21(1):E29

    Article  PubMed  Google Scholar 

  • Tamber S, Cheung AL (2009) SarZ promotes the expression of virulence factors and represses biofilm formation by modulating SarA and agr in Staphylococcus aureus. Infect Immun 77(1):419–428

    Article  CAS  PubMed  Google Scholar 

  • Tu Quoc PH, Genevaux P, Pajunen M, Savilahti H, Georgopoulos C, Schrenzel J, Kelley WL (2007) Isolation and characterization of biofilm formation-defective mutants of Staphylococcus aureus. Infect Immun 75(3):1079–1088

    Article  PubMed  Google Scholar 

  • Zhang XS, García-Contreras R, Wood TK (2007) YcfR (BhsA) influences Escherichia coli biofilm formation through stress response and surface hydrophobicity. J Bacteriol 189(8):3051–3062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by Soonchunhyang University research fund and by Laboratory Safety Management Program, through the National Research Foundation of Korea, funded by the Ministry of Science, ICT and Future Planning (NRF- 2016H1D7A2020904).

Author information

Authors and Affiliations

  1. Department of Medical Sciences, College of Medical Sciences, Soonchunhyang University, Asan, 31538, Republic of Korea

    Seung-Gyun Woo, So-Yeon Lee & Yong-Bin Eom

  2. Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, 22 Soonchunhyang-ro, Asan, Chungcheongnam-do, 31538, Republic of Korea

    So-Min Lee, Kyoung-Hee Lim, Eun-Ju Ha & Yong-Bin Eom

  3. Department of Clinical Laboratory Science, Semyung University, Jaecheon, 27136, Republic of Korea

    Sa-Hyun Kim

Authors
  1. Seung-Gyun Woo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. So-Min Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. So-Yeon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyoung-Hee Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eun-Ju Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sa-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yong-Bin Eom
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong-Bin Eom.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest relevant to this article.

Additional information

Communicated by Erko Stackebrandt.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 151 kb)

Supplementary material 2 (TIFF 211 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Woo, SG., Lee, SM., Lee, SY. et al. The effectiveness of anti-biofilm and anti-virulence properties of dihydrocelastrol and dihydrocelastryl diacetate in fighting against methicillin-resistant Staphylococcus aureus . Arch Microbiol 199, 1151–1163 (2017). https://doi.org/10.1007/s00203-017-1386-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00203-017-1386-x

Keywords

Search

Navigation