Toward development of novel medicines for bacterial infection : Search of biological functions and elucidation of mechanism on occurrence of the functions of c-di-GMP and related compounds

2011 Fiscal Year Final Research Report

• Project/Area Number: 20350076
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemistry related to living body
• Research Institution: Aichi Institute of Technology (2009-2011); Nagoya University (2008)
• Principal Investigator: HAYAKAWA Yoshihiro 愛知工業大学, 工学部, 教授 (50022702)
• Co-Investigator(Kenkyū-buntansha): TSUKAMOTO Masaki 名古屋大学, 大学院・情報科学研究科, 助教 (10362295) ; OHTA Michio 椙山女学園大学, 看護学部, 教授 (20111841) ; YAMADA Keiko 名古屋大学, 大学院・医学研究科, 助教 (00402561)
• Project Period (FY): 2008 – 2011
• Keywords: 核酸・蛋白質・糖化学 / 環状ビス(3'-5')ジグアニル酸 / バイオフィルム / 免疫 / 薬剤耐性菌 / ワクチン

Research Abstract

We have carried out this work aiming to find biological functions of cyclic bis(3'-5') diguanylic acid(c-di-GMP) and related compounds and to elucidate the mechanism on occurrence of the functions. As the result, the work has disclosed that c-di-GMP and some of its derivatives bear bioactivities, which include reduction of infection of methicillin-resistant Staphylococcus aureus(MRSA) by acting as an immunomodulator and vaccine adjuvant. Further, the work has revealed that c-di-GMP binds to stimulator of interferon genes(STING), existing in mammals, to induce immunity ; this discovery will be a keystone for elucidation of mechanism on occurrence of functions of c-di GMP and related compounds.

Research Products

• [Journal Article] STING is a direct innate immune sensor of cyclic dinucleotides (2011)
  • Author(s): Dara L. Burdette, Kathryn M. Monroe, Katia Sotelo-Troha, Barbara Eckert, Mamoru Hyodo, Yoshihiro Hayakawa, and Russell E. Vance
  • Journal Title: Nature Volume: 478 Pages: 515-518
  • Peer Reviewed
• [Journal Article] Cyclic dimeric GMP Signaling Regulates Intracellular Aggregation, Sessility, and Growth of Ehrlichia chaffeensis (2011)
  • Author(s): Yumi Kumagai, Junji Matsuo, Zhihui Cheng, Yoshihiro Hayakawa, and Yasuko Rikihisa
  • Journal Title: Infect. Immun Volume: 79 Pages: 3905-3912
  • Peer Reviewed
• [Journal Article] (2011)
  • Author(s): Joshua E. Pitzer, Syed Z. Sultan, Yoshihiro Hayakawa, Gerry Hobbs, Michael R. Miller, and Md A. Motaleb
  • Journal Title: Infect. Immun Volume: 79 Pages: 1815-1825
  • Peer Reviewed
• [Journal Article] Cyclic di-GMP Signaling Regulates Invasion of Ehrlichia chaffeensis into Human Monocytes (2010)
  • Author(s): Yumi Kumagai, Junji Matsuo, Yoshihiro Hayakawa, and Yasuko Rikihisa
  • Journal Title: J. Bacteriology Volume: 192 Pages: 4122-4133
  • Peer Reviewed
• [Journal Article] Molecular oxygen regulates the enzymatic activity of a heme-containing diguanylate cyclase(HemDGC) for the synthesis of cyclic di-GMP (2010)
  • Author(s): Hitomi Sawai, Shiro Yoshioka, Takeshi Uchidda, Mamoru Hyodo, Yoshihiro Hayakawa, Koichiro Ishimori, and Shigetoshi Aono
  • Journal Title: Biochem. Biophys. Acta Volume: 1804 Pages: 166-172
  • Peer Reviewed
• [Journal Article] Effect of cyclic bis(3'-5') diguanylic acid and its analogs on bacterial biofilm formation (2009)
  • Author(s): Y. Ishihara, M. Hyodo, Y. Hayakawa, T. Kamegaya, K. Yamada, A. Okamoto, T. Hasegawa, and M. Ohta
  • Journal Title: FEMS Microbiology Lett Volume: 301 Pages: 193-200
  • Peer Reviewed
• [Journal Article] A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP (2009)
  • Author(s): Sarah M. McWhirter, Roman Barbalat, Kathryn M. Monroe, Mary F. Fontana, Mamoru Hyodo, Nathalie T. Joncker, Ken J. Ishi, Shizuo Akira, Marco Colonna, Zhijian J. Chen, Katherine A. Fitzgerald, Yoshihiro Hayakawa, and Russell E. Vance
  • Journal Title: J. Exp. Med. Volume: 206 Pages: 1899-1911
  • Peer Reviewed
• [Journal Article] C-di-GMP as a Vaccine Adjuvant Enhances Protection Against Systemic Methicillin-Resistant Staphylococcus aureus(MRSA) Infection Vaccine (2009)
  • Author(s): Dong-Liang Hu, Kouji Narita, Mamoru Hyodo, Yoshihiro Hayakawa, Akio Nakane, and David K. R. Karaolis
  • Journal Title: Vaccine Volume: 27 Pages: 4867-4873
  • Peer Reviewed
• [Journal Article] Anaplasmaa phagocytophilum PleC and PleD diguanylate cyclase two-component system and role of cyclic di-GMP in host-cell infection (2009)
  • Author(s): Tzung-Huei Lai, Yumi Kumagai, Mamoru Hyodo, Yoshihiro Hayakawa, and Yasuko Rikihisa
  • Journal Title: J. Bacteriology Volume: 191 Pages: 693-700
  • Peer Reviewed
• [Journal Article] C-di-GMP is an effective immuno, odulator and vaccine adjuvant against pneumococcal infection (2008)
  • Author(s): A. D. Ogunniyi, J. P. Paton, A. C. Kieby, J. A. McCullers, J. Cook, M. Hyodo, Y. Hayakawa, and D. K. R. Karaolis
  • Journal Title: Vaccine Volume: 26 Pages: 4676-4685
  • Peer Reviewed
• [Journal Article] The N-Ethyl-N-nitrosourea-induced Goldenticket(Gt) Mouse Mutant Reveals an Essential Function of Sting(Tmem173, Mita, Mpys, Eris) in the in vivo Interferon Response to Listeria monocytogenes and Cyclic-di-nucleotides
  • Author(s): John-Demian Sauer, Katia Sotelo-Troha, Jakob von Moltke, Katharyn M. Monroe, Chris S. Rae, Sky W. Brubaker, Mamoru Hyodo, Yoshihiro Hayakawa, Joshua J. Woodward, Daniel A. Portnoy, and Russell E. Vance
  • Journal Title: Infect. Immun Volume: 79(1011) Pages: 688-694
  • Peer Reviewed
• [Presentation] Non-destructive vaporization of GMP facilitated by the phosphoesterification : Conformational preference in the gas phase (2010)
  • Author(s): Hiroya Asami, Ayaka Motoda, Masaki Tsukamoto, Yoshihiro Hayakawa, and Hiroyuki Saigusa
  • Organizer: The 37^<th> International Symposium on Nucleic Acids Chemistry
  • Place of Presentation: Yokohama
  • Year and Date: 2010-11-11
• [Presentation] C-di-GMP produced by E. chaffeensis Regulates Bacterial Internalization into Host Cells and Intracellular Growth (2009)
  • Author(s): Yumi Kumagai, Mamoru Hyodo, Yoshihiro Hayakawa, and Yasuko Rikihisa
  • Organizer: 109th American Society for Microbiology General Meeting
  • Place of Presentation: Philadelphia(U. S. A.)
  • Year and Date: 20090517-21
• [Book] Chemical Properties and Biological Activities of Cyclic Bis(3'-5') diguanylic Acid(c-di-GMP) and Its Analogues. In Modified Nucleosides in Biochemistry, Biotechnology and Medicine (2008)
  • Author(s): Mamoru Hyodo and Yoshihiro Hayakawa
  • Total Pages: 343-363
• [Remarks]
  • URL: http://www.ait-news.jp/111011/index.html
• [Remarks]
  • URL: http://aitech.ac.jp/ac/bc.html
• [Patent(Industrial Property Rights)] 核酸固相合成用リンカー及び担体 (2012)
  • Inventor(s): 塚本眞幸、鈴木紀尊、早川芳宏、前田恵里、森健二郎、味呑憲二郎
  • Industrial Property Rights Holder: 名古屋大学、日東電工(株)
  • Industrial Property Number: 特許、特願2012-016895
  • Filing Date: 2012-01-30
• [Patent(Industrial Property Rights)] 核酸固相合成用リンカー及び担体 (2010)
  • Inventor(s): 早川芳宏、塚本眞幸、森健二郎、味呑憲二郎、前田恵里、小西達也
  • Industrial Property Rights Holder: 名古屋大学、日東電工(株)
  • Industrial Property Number: 特許、12/908, 676
  • Filing Date: 2010-10-20
  • Overseas
• [Patent(Industrial Property Rights)] 核酸固相合成用リンカー及び担体 (2009)
  • Inventor(s): 早川芳宏、塚本眞幸、森健二郎、味呑憲二郎、前田恵里、小西達也
  • Industrial Property Rights Holder: 日東電工株式会社、名古屋大学
  • Industrial Property Number: 特許、特願2009-242445
  • Filing Date: 2009-10-21