Biosynthesis and mechanistic analysis of Trojan-horse antibiotic from Streptomyces species

• Project/Area Number: 18K05385
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 38020:Applied microbiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Asamizu Shumpei 東京大学, 大学院農学生命科学研究科(農学部), 特任講師 (90709057)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: シデロマイシン / 放線菌 / 抗生物質 / 共培養 / ミコール酸含有細菌 / 二次代謝 / 生合成 / シデロフォア / 微生物間相互作用 / 複合培養 / 二次代謝産物 / 二次代謝誘導 / 抗菌薬

Outline of Final Research Achievements

Sideromycin antibiotics are conjugant of siderophore and antibiotic. Sideromycin-like antibiotic HDM was isolated form the combined-culture of Streptomyces sp. HOK021 and Tsukamurella pulmonis TP-B0596. HDM was a chimeric compound of two units; bacterial FabF inhibitor platensimycin and bacterial siderophore enterobactin, connected through thioester bond. In this study, biosynthetic gene clusters for platensimycin and enterobactin was identified from the complete genome sequence of Streptomyces sp. HOK021. Additionally, physicochemical property of sideromycins including HDMs, salmycins, and ferrimycins in LC-MS/MS were elucidated. Obtained knowledge will be applied for further screening to discover novel sideromycin antibiotics.

Academic Significance and Societal Importance of the Research Achievements

天然のシデロマイシン様抗生物質が新たに共培養系から見いだされたことに着想を得た研究を行った。本研究では生産菌のゲノム解析からHDMの生合成機構に関する知見、HDMの他に既存のシデロマイシン類の質量分析における物理化学特性を明らかにすることができたことから、得られた知見を今後の代謝産物未知の微生物培養液からの新規なシデロマイシン系抗生物質の探索に利用できる可能性がある。

Research Products

• [Journal Article] Acyltransferase that catalyses the condensation of polyketide and peptide moieties of goadvionin hybrid lipopeptides (2020)
  • Author(s): Kozakai Ryosuke、Ono Takuto、Hoshino Shotaro、Takahashi Hidenori、Katsuyama Yohei、Sugai Yoshinori、Ozaki Taro、Teramoto Kazuya、Teramoto Kanae、Tanaka Koichi、Abe Ikuro、Asamizu Shumpei、Onaka Hiroyasu
  • Journal Title: Nature Chemistry Volume: 12 Issue: 9 Pages: 869-877
  • DOI: 10.1038/s41557-020-0508-2
  • Peer Reviewed
• [Journal Article] Minimal lactazole scaffold for in vitro thiopeptide bioengineering (2020)
  • Author(s): Vinogradov Alexander A.、Shimomura Morito、Goto Yuki、Ozaki Taro、Asamizu Shumpei、Sugai Yoshinori、Suga Hiroaki、Onaka Hiroyasu
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 2272-2272
  • DOI: 10.1038/s41467-020-16145-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bioactive properties of streptomyces may affect the dominance of Tricholoma matsutake in shiro (2020)
  • Author(s): Vaario Lu-Min、Asamizu Shumpei、Sarjala Tytti、Matsushita Norihisa、Onaka Hiroyasu、Xia Yan、Kurokochi Hiroyuki、Morinaga Shin-Ichi、Huang Jian、Zhang Shijie、Lian Chunlan
  • Journal Title: Symbiosis Volume: 80 Issue: 1 Pages: 1-1
  • DOI: 10.1007/s13199-020-00678-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemical Interactions of Cryptic Actinomycete Metabolite 5‐Alkyl‐1,2,3,4‐tetrahydroquinolines through Aggregate Formation (2019)
  • Author(s): Sugiyama Ryosuke、Nakatani Takahiro、Nishimura Shinichi、Takenaka Kei、Ozaki Taro、Asamizu Shumpei、Onaka Hiroyasu、Kakeya Hideaki
  • Journal Title: Angewandte Chemie International Edition Volume: 58 Issue: 38 Pages: 13486-13491
  • DOI: 10.1002/anie.201905970
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Metabolite Induction via Microorganism Symbiosis and Co-Culturing: A Potential Way to Enhance Chemical Diversity (2019)
  • Author(s): Onaka Hiroyasu、Asamizu Shumpei
  • Journal Title: Comprehensive Natural Products III Volume: - Pages: 487-501
  • DOI: 10.1016/b978-0-12-409547-2.14692-x
  • ISBN: 9780081026915
  • Int'l Joint Research
• [Journal Article] Identification of the common biosynthetic gene cluster for both antimicrobial streptoaminals and antifungal 5-alkyl-1,2,3,4-tetrahydroquinolines (2019)
  • Author(s): Ozaki Taro、Sugiyama Ryosuke、Shimomura Morito、Nishimura Shinichi、Asamizu Shumpei、Katsuyama Yohei、Kakeya Hideaki、Onaka Hiroyasu
  • Journal Title: Organic & Biomolecular Chemistry Volume: 17 Issue: 9 Pages: 2370-2378
  • DOI: 10.1039/c8ob02846j
  • Peer Reviewed
• [Journal Article] Umezawamides, new bioactive polycyclic tetramate macrolactams isolated from a combined-culture of Umezawaea sp. and mycolic acid-containing bacterium (2018)
  • Author(s): Hoshino Shotaro、Wong Chin Piow、Ozeki Masahiro、Zhang Huiping、Hayashi Fumiaki、Awakawa Takayoshi、Asamizu Shumpei、Onaka Hiroyasu、Abe Ikuro
  • Journal Title: The Journal of Antibiotics Volume: 71 Issue: 7 Pages: 653-657
  • DOI: 10.1038/s41429-018-0040-4
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 放線菌複合培養において接触依存性RED 産生に関与するTetR型転写制御因子の解析 (2020)
  • Author(s): 浅水俊平、レイユクン、石塚匠、栁澤昌臣、大野豊、佐藤勝也、尾仲宏康
  • Organizer: QST高崎サイエンスフェスタ2020
• [Presentation] Intergeneric cell-cell contact dependent conversion of bioactive natural products in combined-culture between Streptomyces sp. HEK616 and Tsukamurella pulmonis (2019)
  • Author(s): Shumpei Asamizu
  • Organizer: The 4th A3 Foresight Symposium on Chemical & Synthetic Biology of Natural Products
• [Presentation] Streptomyces sp. HEK616 と Tsukamurella pulmonis との複合培養での二次代謝活性化機構の解析 (2019)
  • Author(s): 浅水 俊平，尾﨑 太郎，西村 慎一，掛谷 秀昭，尾仲 宏康
  • Organizer: 2019年度（第34回）日本放線菌学会北海道大会
• [Presentation] 放線菌の重イオンビーム照射二次代謝非応答性変異株に生じた変異点の遺伝学的解析 (2019)
  • Author(s): 浅水 俊平, 石塚 匠, 栁澤 昌臣, 佐藤 勝也, 大野 豊, 尾仲 宏康
  • Organizer: QST高崎サイエンスフェスタ2019
• [Presentation] 自然共分離放線菌とミコール酸含有細菌の生態学的相互作用の解析 (2019)
  • Author(s): 加藤 愛美，浅水 俊平，尾仲 宏康
  • Organizer: 2019年度（第34回）日本放線菌学会北海道大会
• [Presentation] 複合培養におけるStreptomyces sp. HEK616による5aTHQの生産機構 (2019)
  • Author(s): 浅水 俊平、尾崎 太郎、西村 慎一、掛谷 秀昭、尾仲 宏康
  • Organizer: 2019年度日本農芸化学会
• [Presentation] Combined-culture to activating the production of secondary metabolites in Streptomyces species (2019)
  • Author(s): Shumpei Asamizu, Hiroyasu Onaka
  • Organizer: 2nd China-Japan Joint Symposium on Natural Product Biosynthesis
• [Presentation] 放線菌とミコール酸含有細菌の複合培養 ～抗生物質のトロイの木馬戦略～ (2018)
  • Author(s): 浅水 俊平、アブロリ アグス チャヤ プラマナ、尾仲 宏康
  • Organizer: 第11回北陸合同バイオシンポジウム2018
• [Presentation] Toward the molecular mechanism of mycolic acid-containing bacteria induced actinomycetes specialized metabolism (2018)
  • Author(s): Shumpei Asamizu
  • Organizer: The 3rd A3 Foresight Symposium on Chemical & Synthetic Biology of Natural Products