Journal of Microbiology and Biotechnology

  • 제32권10호
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  • Pages.1284-1291
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  • 2022
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  • 1017-7825(pISSN)
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  • 1738-8872(eISSN)
한국미생물·생명공학회 (The Korean Society for Microbiology and Biotechnology)
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Isovitexin Protects Mice from Methicillin-Resistant Staphylococcus aureus-Induced Pneumonia by Targeting Sortase A

  • Tian, Lili (Institute of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University) ;
  • Wu, Xinliang (Department of Pharmacy, Tianjin Baodi Hospital, Baodi Clinical College, Tianjin Medical University) ;
  • Yu, Hangqian (College of Animal Science, Jilin University) ;
  • Yang, Fengying (Institute of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University) ;
  • Sun, Jian (Department of Animal Husbandry and Veterinary Medicine, Beijing Vocational College Agriculture) ;
  • Zhou, Tiezhong (Institute of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University) ;
  • Jiang, Hong (Institute of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University)
  • 투고 : 2022.06.08
  • 심사 : 2022.09.30
  • 발행 : 2022.10.28
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초록

The rise of methicillin-resistant Staphylococcus aureus (MRSA) has resulted in significant morbidity and mortality, and clinical treatment of MRSA infections has become extremely difficult. Sortase A (SrtA), a virulence determinant that anchors numerous virulence-related proteins to the cell wall, is a prime druggable target against S. aureus infection due to its crucial role in the pathogenicity of S. aureus. Here, we demonstrate that isovitexin, an active ingredient derived from a variety of traditional Chinese medicines, can reversibly inhibit SrtA activity in vitrowith a low dose (IC50=24.72 ㎍/ml). Fluorescence quenching and molecular simulations proved the interaction between isovitexin and SrtA. Subsequent point mutation experiments further confirmed that the critical amino acid positions for SrtA binding to isovitexin were Ala-92, Ile-182, and Trp-197. In addition, isovitexin treatment dramatically reduced S. aureus invasion of A549 cells. This study shows that treatment with isovitexin could alleviate pathological injury and prolong the life span of mice in an S. aureus pneumonia model. According to our research, isovitexin represents a promising lead molecule for the creation of anti-S. aureus medicines or adjuncts.

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과제정보

This work was supported by Science and technology project for people's livelihood of Liaoning province[grant numbers 2021JH2/10200009] the Natural Science Foundation of Liaoning province [grant numbers 20180550687, 2019-ZD-0614]

참고문헌

  1. Diekema DJ, Pfaller MA, Schmitz FJ, Smayevsky J, Bell J, Jones RN, et al. 2001. Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin. Infect. Dis. 32 Suppl 2: S114-132. https://doi.org/10.1086/320184
  2. Turner NA, Sharma-Kuinkel BK, Maskarinec SA, Eichenberger EM, Shah PP, Carugati M, et al. 2019. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nat. Rev. Microbiol. 17: 203-218. https://doi.org/10.1038/s41579-018-0147-4
  3. Smeltzer MS. 2016. Staphylococcus aureus pathogenesis: The importance of reduced cytotoxicity. Trends Microbiol. 24: 681. https://doi.org/10.1016/j.tim.2016.07.003
  4. Zuo QF, Yang LY, Feng Q, Lu DS, Dong YD, Cai CZ, et al. 2013. Evaluation of the protective immunity of a novel subunit fusion vaccine in a murine model of systemic MRSA infection. PLoS One 8: e81212. https://doi.org/10.1371/journal.pone.0081212
  5. Geoghegan JA, Foster TJ. 2015. Cell wall-anchored surface proteins of Staphylococcus aureus: Many proteins, multiple functions. Curr. Topics Microbiol. Immunol. 409: 95-102.
  6. Foster TJ, Hook M. 1998. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6: 484. https://doi.org/10.1016/S0966-842X(98)01400-0
  7. Oliveira D, Borges A, Simoes M. 2018. Staphylococcus aureus toxins and their molecular activity in infectious diseases. Toxins (Basel) 10: 252. https://doi.org/10.3390/toxins10060252
  8. AW M, O S. 2008. Sortase as a target of anti-infective therapy. Pharmacol. Rev. 60: 128-141. https://doi.org/10.1124/pr.107.07110
  9. Mazmanian SK, Liu G, Jensen ER, Lenoy E, Schneewind O. 2000. Staphylococcus aureus sortase mutants defective in the display of surface proteins and in the pathogenesis of animal infections. Proc. Natl. Acad. Sci. USA 97: 5510-5515. https://doi.org/10.1073/pnas.080520697
  10. Wang L, Bi C, Cai H, Liu B, Zhong X, Deng X, et al. 2015. The therapeutic effect of chlorogenic acid against Staphylococcus aureus infection through sortase A inhibition. Front. Microbiol. 6: 1031.
  11. Jonsson IM, 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: 775-780. https://doi.org/10.1016/S1286-4579(03)00143-6
  12. Bubeck Wardenburg J, Patel RJ, Schneewind O. 2007. Surface proteins and exotoxins are required for the pathogenesis of Staphylococcus aureus pneumonia. Infect. Immun. 75: 1040-1044. https://doi.org/10.1128/IAI.01313-06
  13. Jonsson IM, Mazmanian SK, Schneewind O, Verdrengh M, Bremell T, Tarkowski A. 2002. On the role of Staphylococcus aureus sortase and sortase-catalyzed surface protein anchoring in murine septic arthritis. J. Infect. Dis. 185: 1417-1424. https://doi.org/10.1086/340503
  14. Cascioferro S, Totsika M, Schillaci D. 2014. Sortase A: An ideal target for anti-virulence drug development. Microb. Pathog. 77: 105-112. https://doi.org/10.1016/j.micpath.2014.10.007
  15. Maresso AW, Schneewind O. 2008. Sortase as a target of anti-infective therapy. Pharmacol. Rev. 60: 128-141. https://doi.org/10.1124/pr.107.07110
  16. He M, Min JW, Kong WL, He XH, Li JX, Peng BW. 2016. A review on the pharmacological effects of vitexin and isovitexin. Fitoterapia 115: 74-85. https://doi.org/10.1016/j.fitote.2016.09.011
  17. Ganesan K, Xu B. 2017. Molecular targets of vitexin and isovitexin in cancer therapy: a critical review. Ann. NY Acad. Sci. 1401: 102-113. https://doi.org/10.1111/nyas.13446
  18. Mu D, Xiang H, Dong H, Wang D, Wang T. 2018. Isovitexin, a potential candidate inhibitor of sortase A of Staphylococcus aureus USA300. J. Microbiol. Biotechnol. 28: 1426-1432. https://doi.org/10.4014/jmb.1802.02014
  19. Lu C, Zhu J, Wang Y, Umeda A, Cowmeadow RB, Lai E, et al. 2007. Staphylococcus aureus sortase A exists as a dimeric protein in vitro. Biochemistry 46: 9346-9354. https://doi.org/10.1021/bi700519w
  20. Mazmanian SK, Ton-That H, Su K, Schneewind O. 2002. An iron-regulated sortase anchors A class of surface protein during Staphylococcus aureus pathogenesis. Proc. Natl. Acad. Sci. USA 99: 2293-2298. https://doi.org/10.1073/pnas.032523999
  21. Ton-That H, Liu G, Mazmanian SK, Faull KF, Schneewind O. 1999. Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif. Proc. Natl. Acad. Sci. USA 96: 12424-12429. https://doi.org/10.1073/pnas.96.22.12424
  22. Kim D, Park J, Kim J, Han C, Yoon J, Kim N, et al. 2006. Flavonoids as mushroom tyrosinase inhibitors: a fluorescence quenching study. J. Agric. Food Chem. 54: 935-941. https://doi.org/10.1021/jf0521855
  23. Trott O, Olson AJ. 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31: 455-461.
  24. Pierce LC, Salomon-Ferrer R, Augusto F. de Oliveira C, McCammon JA, Walker RC. 2012. Routine access to millisecond time scale events with accelerated molecular dynamics. J. Chem. Theory Comput. 8: 2997-3002. https://doi.org/10.1021/ct300284c
  25. Gotz AW, Williamson MJ, Xu D, Poole D, Le Grand S, Walker RC. 2012. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 1. Generalized born. J. Chem. Theory Comput. 8: 1542-1555. https://doi.org/10.1021/ct200909j
  26. Salomon-Ferrer R, Gotz AW, Poole D, Le Grand S, Walker RC. 2013. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. explicit solvent particle mesh Ewald. J. Chem. Theory Comput. 9: 3878-3888. https://doi.org/10.1021/ct400314y
  27. Niu X, Qiu J, Wang X, Gao X, Dong J, Wang J, et al. 2013. Molecular insight into the inhibition mechanism of cyrtominetin to αhemolysin by molecular dynamics simulation. Eur. J. Med. Chem. 62: 320-328. https://doi.org/10.1016/j.ejmech.2013.01.008
  28. Marraffini LA, DeDent AC, Schneewind O. 2006. Sortases and the art of anchoring proteins to the envelopes of Gram-positive bacteria. Microbiol. Mol. Biol. Rev. 70: 192-221. https://doi.org/10.1128/MMBR.70.1.192-221.2006
  29. Wang L, Li Q, Li J, Jing S, Jin Y, Yang L, et al. 2021. Eriodictyol as a potential candidate inhibitor of sortase A protects mice from methicillin-resistant Staphylococcus aureus-induced pneumonia. Front. Microbiol. 12: 635710. https://doi.org/10.3389/fmicb.2021.635710
  30. Chen S, Paterson GK, Tong HH, Mitchell TJ, DeMaria TF. 2005. Sortase A contributes to pneumococcal nasopharyngeal colonization in the chinchilla model. FEMS Microbiol. Lett. 253: 151-154. https://doi.org/10.1016/j.femsle.2005.09.052
  31. Dan Mu, Hua Xiang, Haisi Dong, Wang D, Wang T. 2018. Isovitexin, a potential candidate inhibitor of sortase A of Staphylococcus aureus USA300. J. Microbiol. Biotechnol. 28: 1426-1432. https://doi.org/10.4014/jmb.1802.02014