Search for natural products which inhibit Entamoeba histolytica NAD kinase

• Project/Area Number: 17K08344
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Natural medicines
• Research Institution: Kitasato University
• Principal Investigator: Mori Mihoko 北里大学, 感染制御科学府, 助教 (20425648)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Entamoeba histolytica / NAD kinase / 微生物二次代謝産物 / 天然化合物 / 赤痢アメーバ / アメーバ赤痢 / 微生物培養液 / 微生物代謝産物 / 化合物ライブラリー

Outline of Final Research Achievements

Amebiasis is a diarrheal disease in human, caused by infection with the protozoan parasite Entamoeba histolytica. Metronidazole has been a drug of choice against amebiasis for decades, however, this drug has several side effects and the resistant strain has been reported. Therefore, new drugs with different modes of action or targets have been needed. In this study, we established the screening system for inhibitors against E. histolytica NAD kinase. E. histolytica NAD kinase has the unique character and the essentiality of its gene has been confirmed. Although the screening for Eh NADK inhibitors was conducted using microbial broth extracts, no sample showed the inhibition. Concurrently we screened antiamebic samples using microbial broth extracts. We found chartreusin as an antiamebic compound with ED50 = 100 microM from a broth extract of one Streptomyces strain, and found tenuazonic acid as an antiamebic compound with ED50 = 50 microM from a broth extract of Aspergillus nomius.

Academic Significance and Societal Importance of the Research Achievements

本研究において赤痢アメーバのNAD kinaseを阻害する微生物培養液を見出すことができなかった。評価法あるいは微生物培養液の調製法を見直す必要があると考えられた。並行して行った赤痢アメーバ原虫を用いた殺虫活性評価では複数の殺虫活性化合物が得られた。本研究において、赤痢アメーバ原虫の細胞選択的に毒性を示し、多くの種類の微生物が生産する化合物に関する知見を蓄積できた。今後の新規赤痢アメーバ症治療薬探索研究に活用されるよう本知見を論文として発表する。

Research Products

• [Int'l Joint Research] パスツール研究所(フランス)
• [Int'l Joint Research] インドネシア技術評価応用庁/アイルランガ大学(インドネシア)
• [Int'l Joint Research] インドネシア技術評価応用庁(インドネシア)
• [Int'l Joint Research] 技術評価応用庁/インドネシア科学院/アイルランガ大学(インドネシア)
• [Journal Article] Discovery of Antiamebic Compounds That Inhibit Cysteine Synthase From the Enteric Parasitic Protist Entamoeba histolytica by Screening of Microbial Secondary Metabolites (2018)
  • Author(s): Mihoko Mori, Satoshi Tsuge, Wataru Fukasawa, Ghulam Jeelani, Kumiko Nakada-Tsukui, Kenichi Nonaka, Atsuko Matsumoto, Satoshi Omura, Tomoyoshi Nozaki and Kazuro Shiomi
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 8 Pages: 1-9
  • DOI: 10.3389/fcimb.2018.00409
  • Peer Reviewed / Open Access
• [Journal Article] Characterization and validation of Entamoeba histolytica pantothenate kinase as a novel anti-amebic drug target. (2018)
  • Author(s): Nurkanto, A.; Jeelani, G.; Yamamoto, T.; Suematsu, M.; Naito, Y.; Hishiki, T.; Mori, M.; Shiomi, K.; Hashimoto, T.; Nozaki, T.
  • Journal Title: International journal for parasitology. Drugs and drug resistance Volume: 8 Pages: 125-136
  • NAID: 120007134287
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biochemical studies of membrane bound Plasmodium falciparum mitochondrial L -malate:quinone oxidoreductase, a potential drug target (2018)
  • Author(s): Hartuti, E. D.; Inaoka, D. K.; Komatsuya, K.; Miyazaki, Y.; Miller, R. J.; Wang, X.; Sadikin, M.; Prabandari, E. E.; Waluyo, D.; Kuroda, M.; Amalia, E.; Matsuo, Y.; Nugroho, N. B.; Saimoto, H.; Pramisandi, A.; Watanabe, Y.; Mori, M.; Shiomi, K.; Balogun, E. O.; Shiba, T.; Harada, S.; Nozaki, T.; Kita, K
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Bioenergetics Volume: 1859 Issue: 3 Pages: 191-200
  • DOI: 10.1016/j.bbabio.2017.12.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of novel antiviral of fungus-derived brefeldin A against dengue viruses (2017)
  • Author(s): Raekiansyah Muhareva、Mori Mihoko、Nonaka Kenichi、Agoh Masanobu、Shiomi Kazuro、Matsumoto Atsuko、Morita Kouichi
  • Journal Title: Tropical Medicine and Health Volume: 45 Issue: 1 Pages: 32-38
  • DOI: 10.1186/s41182-017-0072-7
  • NAID: 120006987373
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 1-Methoxypyrrole-2-carboxamide - A new pyrrole compound isolated from Streptomyces griseocarneus SWW368 (2017)
  • Author(s): Wattanasuepsin, W.; Intra, B.; Panbangred, W.; Euanorasetr, J.; Watanabe, Y.; Fukasawa, W.; Mingma, R.; Mori, M.; Matsumoto, A.; Shiomi, K.
  • Journal Title: Journal of General and Applied Microbiology Volume: 63 Pages: 207-211
  • NAID: 130006067743
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Antiamebic compounds produced by Indonesian microbial strains. (2019)
  • Author(s): Mori M, Nurkanto A, Hidayati DN, Dewi D, Nonaka K, Matsumoto A, Waluyo D, Wibowo AE, Shiomi, K, Nozaki, T
  • Organizer: Asian Mycological Congress 2019
  • Int'l Joint Research
• [Presentation] Ovalicin, a fungal metabolite, is effective against a hamster amebic liver abscess model. (2019)
  • Author(s): Mori M, Saito-Nakamo Y, Tsuge S, Omura S, Shiomi, K, Nozaki, T
  • Organizer: Asia Infectious Disease Project Joint Symposium
  • Int'l Joint Research
• [Presentation] インドネシア微生物資源からの抗赤痢アメーバ化合物の探索. (2019)
  • Author(s): 森美穂子, Nurkanto, A., 山下道雄、Waluyo, D., Pramisandi, A., 土橋和之、大村智、塩見和朗、野崎智義.
  • Organizer: 日本農芸化学会2019年度大会
• [Presentation] インドネシア微生物資源からの抗赤痢アメーバ化合物の探索 (2019)
  • Author(s): 森美穂子、Arif Nurkanto、山下 道雄、Danang Waluyo、Amila Pramisandi、土橋 和之、大村 智、塩見 和朗、野崎 智義
  • Organizer: 日本農芸化学会2019年度大会
• [Presentation] Ovalicin, a fungal metabolite, is effective against a hamster amebic liver abscess model. (2018)
  • Author(s): Mihoko Mori, Yumiko Saito-Nakano, Satoshi Tsuge, Satoshi Omura, Kazuro Shiomi, Tomoyoshi Nozaki
  • Organizer: XIX International Seminor On Amebiasis 2018
  • Int'l Joint Research
• [Presentation] 糸状菌代謝産物 ovalicin は赤痢アメーバ症肝膿瘍モデルハムスターに対して治療効果を示す (2017)
  • Author(s): 森美穂子
  • Organizer: 2017年度第2回農芸化学会関東支部例会
  • Invited