Applied Microbiology and Biotechnology

, Volume 102, Issue 24, pp 10665–10674 | Cite as

Phloretin reduces cell injury and inflammation mediated by Staphylococcus aureus via targeting sortase B and the molecular mechanism

  • Guizhen Wang
  • Yawen Gao
  • Hongsu Wang
  • Jianfeng WangEmail author
  • Xiaodi NiuEmail author
Applied microbial and cell physiology


Sortase B (SrtB) is a vital virulence factor that plays a critical role in Staphylococcus aureus (S. aureus) infections, indicating that it could be a latent target for S. aureus infections. In this study, phloretin, a natural compound that primarily exists in the pericarp and velamen of apples and pears, shows little anti-S. aureus activity, but significantly inhibited SrtB activity in vitro. The results of lactate dehydrogenase release and live/dead cell assays suggested that phloretin reduced human alveolar epithelial cell damage caused by S. aureus. Additionally, an adhesion assay confirmed that phloretin lowered the colony count of S. aureus in human alveolar cells. Phloretin treatment significantly attenuated the inflammatory response in macrophage cells (J774) co-cultured with S. aureus as determined by an enzyme-linked immune-sorbent assay. Furthermore, the results of molecular dynamics simulation, site-directed mutagenesis, and fluorescence spectroscopy quenching indicated that phloretin was directly located in the active pocket of SrtB and blocked substrate binding, leading to the loss of SrtB activity. These results indicate that phloretin is a possible candidate for treatment of S. aureus infections.


Staphylococcus aureus Phloretin Sortase B Cytotoxicity Adhesion Inflammation Molecular simulations 


Author contributions

X.D.N. and J.F.W. conceived and designed the experiments. G.Z.W. and Y.W.G. performed the experiments. H.S.W. and Y.W.G contributed reagents/materials/analysis tools. X.D.N., J.F.W., and G.Z.W. wrote the paper.


This work was supported by the National Nature Science Foundation of China [Grant No. 31402251, 31602109 to H.S.W] and the National Nature Science Foundation of China [Grant No. 31572566 to X.D.N].

Compliance with ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

253_2018_9376_MOESM1_ESM.pdf (771 kb)
ESM 1 (PDF 770 kb)


  1. Cascioferro S, Cusimano MG, Schillaci D (2014) Antiadhesion agents against Gram-positive pathogens. Future Microbiol 9(10):1209–1220CrossRefGoogle Scholar
  2. Chambers HF, DeLeo FR (2009) Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 7(9):629–641. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Dong J, Qiu J, Wang J, Li H, Dai X, Zhang Y, Wang X, Tan W, Niu X, Deng X, Zhao S (2013) Apigenin alleviates the symptoms of Staphylococcus aureus pneumonia by inhibiting the production of alpha-hemolysin. FEMS Microbiol Lett 338(2):124–131. CrossRefPubMedGoogle Scholar
  4. Grigg JC, Ukpabi G, Gaudin CF, Murphy ME (2010) Structural biology of heme binding in the Staphylococcus aureus Isd system. J Inorg Biochem 104(3):341–348CrossRefGoogle Scholar
  5. Hiramatsu K, Katayama Y, Matsuo M, Sasaki T, Morimoto Y, Sekiguchi A, Baba T (2014) Multi-drug-resistant Staphylococcus aureus and future chemotherapy. J Infect Chemother 20(10):593–601CrossRefGoogle Scholar
  6. Jacobitz AW, Wereszczynski J, Yi SW, Amer BR, Huang GL, Nguyen AV, Sawaya MR, Jung ME, Mccammon JA, Clubb RT (2014) Structural and computational studies of the Staphylococcus aureus sortase B-substrate complex reveal a substrate-stabilized oxyanion hole. J Biol Chem 289(13):8891–8902CrossRefGoogle Scholar
  7. Jonsson I-M, Mazmanian SK, Schneewind O, Bremell T, Tarkowski A (2003) The role of Staphylococcus aureus sortase A and sortase B in murine arthritis. Microbes Infect 5(9):775–780. CrossRefPubMedGoogle Scholar
  8. Kang SS, Kim JG, Lee TH, Oh KB (2006) Flavonols inhibit sortases and sortase-mediated Staphylococcus aureus clumping to fibrinogen. Biol Pharm Bull 29(8):1751–1755CrossRefGoogle Scholar
  9. Li H, Chen Y, Zhang B, Niu X, Song M, Luo Z, Lu G, Liu B, Zhao X, Wang J (2016) Inhibition of sortase A by chalcone prevents Listeria monocytogenes infection. Biochem Pharmacol 106:19–29CrossRefGoogle Scholar
  10. Liu M, Tanaka WN, Zhu H, Xie G, Dooley DM, Lei B (2008) Direct hemin transfer from IsdA to IsdC in the iron-regulated surface determinant (Isd) heme acquisition system of Staphylococcus aureus. J Biol Chem 283(11):6668–6676CrossRefGoogle Scholar
  11. Maresso AW, Schneewind O (2006) Iron acquisition and transport in Staphylococcus aureus. Biometals 19(2):193–203CrossRefGoogle Scholar
  12. Oh KB, Oh MN, Kim JG, Shin DS, Shin J (2006) Inhibition of sortase-mediated Staphylococcus aureus adhesion to fibronectin via fibronectin-binding protein by sortase inhibitors. Appl Microbiol Biotechnol 70(1):102–106CrossRefGoogle Scholar
  13. Prestinaci F, Pezzotti P, Pantosti A (2015) Antimicrobial resistance: a global multifaceted phenomenon. Pathog Glob Health 109(7):309–318. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Qiu J, Niu X, Wang J, Xing Y, Leng B, Dong J, Li H, Luo M, Zhang Y, Dai X, Luo Y, Deng X (2012) Capsaicin protects mice from community-associated methicillin-resistant Staphylococcus aureus pneumonia. PLoS One 7(3):e33032. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Rasko DA, Sperandio V (2010) Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov 9(2):117–128CrossRefGoogle Scholar
  16. Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S, Cohen J, Findlay D, Gyssens I, Heuer OE, Kahlmeter G, Kruse H, Laxminarayan R, Liebana E, Lopez-Cerero L, MacGowan A, Martins M, Rodriguez-Bano J, Rolain JM, Segovia C, Sigauque B, Tacconelli E, Wellington E, Vila J (2015) The global threat of antimicrobial resistance: science for intervention. New Microbes New Infect 6:22–29. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Schillaci D, Spano V, Parrino B, Carbone A, Montalbano A, Barraja P, Diana P, Cirrincione G, Cascioferro S (2017) Pharmaceutical approaches to target antibiotic resistance mechanisms. J Med Chem 60(20):8268–8297. CrossRefPubMedGoogle Scholar
  18. Song M, Teng Z, Li M, Niu X, Wang J, Deng X (2017) Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A. J Cell Mol Med 21(10):2586–2598. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Villareal VA, Spirig T, Robson SA, Liu M, Lei B, Clubb RT (2011) Transient weak protein-protein complexes transfer heme across the cell wall of Staphylococcus aureus. J Am Chem Soc 133(36):14176–14179CrossRefGoogle Scholar
  20. Wang J, Zhou X, Liu S, Li G, Zhang B, Deng X, Niu X (2015) Novel inhibitor discovery and the conformational analysis of inhibitors of listeriolysin O via protein-ligand modeling. Sci Rep 5:8864. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Wang J, Zhou X, Li W, Deng X, Deng Y, Niu X (2016) Curcumin protects mice from Staphylococcus aureus pneumonia by interfering with the self-assembly process of alpha-hemolysin. Sci Rep 6:28254. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Wang J, Liu B, Teng Z, Zhou X, Wang X, Zhang B, Lu G, Niu X, Yang Y, Deng X (2017) Phloretin attenuates Listeria monocytogenes virulence both in vitro and in vivo by simultaneously targeting listeriolysin O and sortase A. Front Cell Infect Microbiol 7:9. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Zong Y, Mazmanian SK, Schneewind O, Narayana SVL (2004) The structure of sortase B, a cysteine transpeptidase that tethers surface protein to the Staphylococcus aureus cell wall. Structure 12(1):105–112. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of Food Science and EngineeringJilin UniversityChangchunChina
  2. 2.Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary MedicineJilin UniversityChangchunChina

Personalised recommendations