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The direct anti-MRSA effect of emodin via damaging cell membrane

  • Applied microbial and cell physiology
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Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) has become an important bacterium for nosocomial infection. Only a few antibiotics can be effective against MRSA. Therefore, searching for new drugs against MRSA is important. Herein, anti-MRSA activities of emodin and its mechanisms were investigated. Firstly, in vitro antimicrobial activity was investigated by minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and time-growth curve, and multipassage resistance testing was performed. Secondly, protection of emodin on mice survival and blood bacterial load in mice challenged with lethal or sublethal dose of MRSA were investigated. Subsequently, the influences of emodin on the bacterial morphology, messenger RNA (mRNA) expressions related to cell wall synthesis and lysis, β-lactamase activity, drug accumulation, membrane fluidity, and integrity were performed to investigate its mechanisms. Lastly, in vitro cytotoxicity assay were performed using the 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) method. The results showed MICs and MBCs of emodin against MRSA252 and 36 clinical MRSA strains were among 2–8 and 4–32 μg/mL, respectively. There was no MIC increase for emodin during 20 passages. In vivo, emodin dose-dependently protected mice challenged with lethal dose of MRSA and decreased bacterial load in mice challenged with sublethal dose of MRSA. Morphology observation showed emodin might disrupt cell wall and membrane of MRSA. Although emodin had no influence on genes related to cell wall synthesis and lysis as well as β-lactamase activity and drug accumulation, emodin reduced membrane fluidity and disrupted membrane integrity. Based on the fact that emodin had no significant cytotoxicity against mammalian cells, it could be further investigated as a membrane-damage bactericide against MRSA in the future.

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References

  • Alves DS, Perez-Fons L, Estepa A, Micol V (2004) Membrane-related effects underlying the biological activity of the anthraquinones emodin and barbaloin. Biochem Pharmacol 68:549–561

    Article  CAS  PubMed  Google Scholar 

  • Archer GL, Bosilevac JM (2001) Signaling antibiotic resistance in staphylococci. Science 291:1915–1916

    Article  CAS  PubMed  Google Scholar 

  • Bardak-Ozcem S, Turhan T, Sipahi OR, Arda B, Pullukcu H, Yamazhan T, Isikgoz-Tasbakan M, Sipahi H, Ulusoy S (2013) Daptomycin versus vancomycin in treatment of methicillin-resistant Staphylococcus aureus meningitis in an experimental rabbit mode. Antimicrob Agents Chemother 57:1556–1558

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bernal P, Lemaire S, Pinho MG, Mobashery S, Hinds J, Taylor PW (2010) Insertion of epicatechin gallate into the cytoplasmic membrane of methicillin-resistant Staphylococcus aureus disrupts penicillin-binding protein (PBP) 2a-mediated beta-lactam resistance by delocalizing PBP2. J Biol Chem 285:24055–24065

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Caturla N, Vera-Samper E, Villalain J, Mateo CR, Micol V (2003) The relationship between the antioxidant and the antibacterial properties of galloylated catechins and the structure of phospholipid model membranes. Free Radic Biol Med 34:648–662

    Article  CAS  PubMed  Google Scholar 

  • Clinical Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. In: Twenty-First Informational Supplement 2012, M100-S22

  • Farrell DJ, Robbins M, Rhys-Williams W, Love WG (2011) Investigation of the potential for mutational resistance to XF-73, retapamulin, mupirocin, fusidic acid, daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus isolates during a 55-passage study. Antimicrob Agents Chemother 55:1177–1181

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fuda CC, Fisher JF, Mobashery S (2005) Beta-lactam resistance in Staphylococcus aureus: the adaptive resistance of a plastic genome. Cell Mol Life Sci 62:2617–2633

    Article  CAS  PubMed  Google Scholar 

  • He L, Bi JJ, Guo Q, Yu Y, Ye XF (2012) Effects of emodin extracted from Chinese herbs on proliferation of non-small cell lung cancer and underlying mechanisms. Asian Pac J Cancer Prev 13:1505–1510

    Article  PubMed  Google Scholar 

  • Hurdle JG, O’Neill AJ, Chopra I, Lee RE (2011) Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol 9:62–75

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jiang W, Li B, Zheng X, Liu X, Cen Y, Li J, Pan X, Cao H, Zheng J, Zhou H (2011) Artesunate in combination with oxacillin protect sepsis model mice challenged with lethal live methicillin-resistant Staphylococcus aureus (MRSA) via its inhibition on proinflammatory cytokines release and enhancement on antibacterial activity of oxacillin. Int Immunopharmacol 11:1065–1073

    Article  CAS  PubMed  Google Scholar 

  • Koh JJ, Qiu S, Zou H, Lakshminarayanan R, Li J, Zhou X, Tang C, Saraswathi P, Verma C, Tan DT, Tan AL, Liu S, Beuerman RW (2013) Rapid bactericidal action of alpha-mangostin against MRSA as an outcome of membrane targeting. Biochim Biophys Acta 1828:834–844

    Article  CAS  PubMed  Google Scholar 

  • Lee YS, Kang OH, Choi JG, Oh YC, Keum JH, Kim SB, Jeong GS, Kim YC, Shin DW, Kwon DY (2010) Synergistic effect of emodin in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Pharm Biol 48:1285–1290

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Li Q, Du Y, Jiang X, Tang J, Wang J, Li G, Jiang Y (2008) Prevalence of plasmid-mediated AmpC beta-lactamases in a Chinese university hospital from 2003 to 2005: first report of CMY-2-Type AmpC beta-lactamase resistance in China. J Clin Microbiol 4:1317–1321

    Article  Google Scholar 

  • Li B, Yao Q, Pan XC, Wang N, Zhang R, Li J, Ding G, Liu X, Wu C, Ran D, Zheng J, Zhou H (2011) Artesunate enhances the antibacterial effect of {beta}-lactam antibiotics against Escherichia coli by increasing antibiotic accumulation via inhibition of the multidrug efflux pump system AcrAB-TolC. J Antimicrob Chemother 66:769–777

    Article  CAS  PubMed  Google Scholar 

  • Li XL, Liu D, Liu X, Jiang WW, Zhou WY, Yan W, Cen YY, Li B, Cao GQ, Ding GF, Pang XL, Sun JG, Zheng J, Zhou H (2012) CpG ODN107 potentiates radiosensitivity of human glioma cells via TLR9-mediated NF-κB activation and NO production. Tumor Biol 5:1607–1618

    Article  Google Scholar 

  • Li XX, Dong Y, Wang W, Wang HL, Chen YY, Shi GY, Yi J, Wang J (2013) Emodin as an effective agent in targeting cancer stem-like side population cells of gallbladder carcinoma. Stem Cells Dev 22:554–566

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K (2015) A new antibiotic kills pathogens without detectable resistance. Nature 7535:455–459

    Article  Google Scholar 

  • Livermore DM (2000) Antibiotic resistance in staphylococci. Int J Antimicrob Agents 16(Suppl 1):S3–10

    Article  CAS  PubMed  Google Scholar 

  • Ma L, Li W (2014) Emodin inhibits LOVO colorectal cancer cell proliferation via the regulation of the Bcl-2/Bax ratio and cytochrome. Exp Ther Med 4:1225–1228

    Google Scholar 

  • Nguyen F, Starosta AL, Arenz S, Sohmen D, Donhofer A, Wilson DN (2014) Tetracycline antibiotics and resistance mechanisms. Biol Chem 395:559–575

    Article  CAS  PubMed  Google Scholar 

  • Pinho MG, Errington J (2005) Recruitment of penicillin-binding protein PBP2 to the division site of Staphylococcus aureus is dependent on its transpeptidation substrates. Mol Microbiol 55:799–807

    Article  CAS  PubMed  Google Scholar 

  • Qin R, Xiao K, Li B, Jiang W, Peng W, Zheng J, Zhou H (2013) The combination of catechin and epicatechin gallate from fructus crataegi potentiates beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) in vitro and in vivo. Int J Mol Sci 14:1802–1821

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sader HS, Jones RN, Rossi KL, Rybak MJ (2009) Occurrence of vancomycin-tolerant and heterogeneous vancomycin-intermediate strains (hVISA) among Staphylococcus aureus causing bloodstream infections in nine USA hospitals. J Antimicrob Chemother 64(5):1024–1028

  • Scheffers DJ, Pinho MG (2005) Bacterial cell wall synthesis: new insights from localization studies. Microbiol Mol Biol Rev 69:585–607

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shan B, Cai YZ, Brooks JD, Corke H (2008) Antibacterial properties of Polygonum cuspidatum roots and their major bioactive constituents. Food Chem 3:530–537

    Article  Google Scholar 

  • Sui JQ, Xie KP, Zou W, Xie MJ (2014) Emodin inhibits breast cancer cell proliferation through the ERalpha-MAPK/Akt-cyclin D1/Bcl-2 signaling pathway. Asian Pac J Cancer Prev 15:6247–6251

    Article  PubMed  Google Scholar 

  • Tanaka M, Mroz P, Dai T, Huang L, Morimoto Y, Kinoshita M, Yoshihara Y, Shinomiya N, Seki S, Nemoto K (2013) Linezolid and vancomycin decrease the therapeutic effect of methylene blue-photodynamic therapy in a mouse model of MRSA bacterial arthritis. Photochem Photobiol 89:679–682

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tazi A, Chapron J, Touak G, Longo M, Hubert D, Collobert G, Dusser D, Poyart C, Morand PC (2013) Rapid emergence of resistance to linezolid and mutator phenotypes in Staphylococcus aureus isolates from an adult cystic fibrosis patient. Antimicrob Agents Chemother 57:5186–5188

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tian K, Zhang H, Chen X, Hu Z (2006) Determination of five anthraquinones in medicinal plants by capillary zone electrophoresis with beta-cyclodextrin addition. J Chromatogr A 1123:134–137

    Article  CAS  PubMed  Google Scholar 

  • Wright GD (2007) The antibiotic resistome: the nexus of chemical and genetic diversity. Nat Rev Microbiol 5:175–186

    Article  CAS  PubMed  Google Scholar 

  • Zhao LM, Zhang LM, Liu JJ, Wan LJ, Chen YQ, Zhang SQ, Yan ZW, Jiang JH (2012) Synthesis and antitumor activity of conjugates of 5-Fluorouracil and emodin. Eur J Med Chem 1:255–260

    Article  Google Scholar 

Download references

Acknowledgments

This research was supported by a grant from the Science Research Foundation of the Third Military Medical University 2009XYY07. We thank all colleagues in Medical Research Center for technical assistance.

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Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Ming Liu, Wei Peng, Rongxin Qin, Zifei Yan, Yanyan Cen, Xichun Pan, Weiwei Jiang, Bin Li, Xiaoli Li & Hong Zhou

  2. Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Xinchuan Zheng

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  1. Ming Liu
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  2. Wei Peng
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  3. Rongxin Qin
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  11. Hong Zhou
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Correspondence to Hong Zhou.

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Liu, M., Peng, W., Qin, R. et al. The direct anti-MRSA effect of emodin via damaging cell membrane. Appl Microbiol Biotechnol 99, 7699–7709 (2015). https://doi.org/10.1007/s00253-015-6657-3

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