Mechanisms of Bacterial Competition and Coordination: Adaptation to Hostile Environments

• Project/Area Number: 18K19451
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Osaka University
• Principal Investigator: Nishino Kunihiko 大阪大学, 産業科学研究所, 教授 (30432438)
• Project Period (FY): 2018-06-29 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 腸内細菌 / 異物排出 / トランスポーター / インドール / 胆汁酸 / 脂肪酸 / サルモネラ / 大腸菌 / 異種細菌 / 薬剤排出 / 耐性 / TolC / EmrAB / AcrAB / 検出 / tnaAB / 環境適応 / ポンプ / 系統解析 / 進化 / 阻害剤 / インフルエンザ菌 / 細菌 / 競合 / 協調 / 宿主

Outline of Final Research Achievements

This project aims to identify the signaling networks among heterologous bacteria and to elucidate the interactions between the molecules forming the networks and the signaling molecules and substances present in the host environment, and to detect and identify the mechanisms of competition and cooperation among heterologous bacteria and the substances present in them. In this study, regarding the drug efflux pumps that are involved in adaptation to the host environment and survival in the presence of heterologous bacteria, we conducted analyses on phylogenetic development of hundreds of pumps in heterologous bacteria, clarified the different roles of the pumps in different bacterial species, and elucidated their involvement in bile acid and fatty acid resistance. We also succeeded in detecting indole, which is produced by some bacteria in the intestine, by a method that does not rely on conventional extraction or enrichment.

Academic Significance and Societal Importance of the Research Achievements

これまで細菌の異物排出トランスポーターは、耐性化を理解するため研究が進められてきた。本研究により、胆汁酸や脂肪酸への抵抗性に関与していることが明らかになり、様々な細菌が生存している環境において、環境に応答するたにもトランスポーターが必要であることが分かった。さらに、数百種におよぶ系統解析は、他細菌や生物種に存在する未知のトランスポーターをより簡便に分類するためのツールとして役立つ。また、宿主環境適応におけるトランスポーターの生理的役割を理解する上でも役立つものである。さらに、腸内細菌が産生するインドールを簡便に検出する方法を開発した。成果は、細菌恒常性を破綻させることのできる創薬にもつながる。

Research Products

• [Int'l Joint Research] ユストゥス・リービッヒ大学ギーセン(ドイツ)
• [Int'l Joint Research] ゲント大学(ベルギー)
• [Journal Article] Analysis of multidrug efflux transporters in resistance to fatty acid salts reveals a TolC-independent function of EmrAB in Salmonella enterica (2022)
  • Author(s): Yoneda Tomohiro、Sakata Hiroki、Yamasaki Seiji、Hayashi-Nishino Mitsuko、Nishino Kunihiko
  • Journal Title: PLOS ONE Volume: 17 Issue: 4 Pages: e0266806-e0266806
  • DOI: 10.1371/journal.pone.0266806
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in the Phenicol Exporter Gene fexA Impact Resistance Levels in Three Bacterial Hosts According to Susceptibility Testing and Protein Modeling (2022)
  • Author(s): M?ller Anja、Sakurai Keisuke、Seinige Diana、Nishino Kunihiko、Kehrenberg Corinna
  • Journal Title: Frontiers in Microbiology Volume: 12 Pages: 794435-794435
  • DOI: 10.3389/fmicb.2021.794435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of Genetic Variants via Bacterial Respiration Gas Analysis (2020)
  • Author(s): Koga Naoki、Hosomi Takuro、Zwama Martijn、Jirayupat Chaiyanut、Yanagida Takeshi、Nishino Kunihiko、Yamasaki Seiji
  • Journal Title: Frontiers in Microbiology Volume: 11 Pages: 581571-581571
  • DOI: 10.3389/fmicb.2020.581571
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 多剤排出ポンプの機能と阻害機構 (2020)
  • Author(s): 西野邦彦、山崎聖司、中島良介
  • Journal Title: 膜タンパク質工学ハンドブック Volume: 1-2-13 Pages: 83-92
• [Journal Article] Phylogenetic and functional characterisation of the Haemophilus influenzae multidrug efflux pump AcrB (2019)
  • Author(s): Zwama Martijn、Yamaguchi Akihito、Nishino Kunihiko
  • Journal Title: Communications Biology Volume: 2 Issue: 1 Pages: 340-340
  • DOI: 10.1038/s42003-019-0564-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of a structure determination method using a multidrug-resistance regulator protein as a framework (2019)
  • Author(s): Matsumoto Takashi、Nakashima Ryosuke、Yamano Akihito、Nishino Kunihiko
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 518 Issue: 2 Pages: 402-408
  • DOI: 10.1016/j.bbrc.2019.08.070
  • Peer Reviewed / Open Access
• [Journal Article] The Salmonella Enteritidis TolC outer membrane channel is essential for egg white survival (2019)
  • Author(s): Raspoet R.、Eeckhaut V.、Vermeulen K.、De Smet L.、Wen Y.、Nishino K.、Haesebrouck F.、Ducatelle R.、Devreese B.、Van Immerseel F.
  • Journal Title: Poultry Science Volume: 98 Issue: 5 Pages: 2281-2289
  • DOI: 10.3382/ps/pey584
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 細菌薬剤排出ポンプと耐性菌新規判別手法 (2022)
  • Author(s): 西野邦彦
  • Organizer: 第56回 緑膿菌感染症学会
  • Invited
• [Presentation] 抗菌薬標的としての細菌薬剤排出ポンプ (2021)
  • Author(s): 西野邦彦
  • Organizer: 日本細菌学会総会
  • Invited
• [Presentation] Function and Regulation of Bacterial Multidrug Efflux Pumps (2020)
  • Author(s): Kunihiko Nishino
  • Organizer: Croucher Advanced Study Institute 2020 Metals in Biology and Medicine: From Molecular Image to Drug Resistance
  • Int'l Joint Research / Invited
• [Presentation] Crystal structure of the multidrug resistance regulator RamR complexed with bile acids (2019)
  • Author(s): S. Yamasaki, R. Nakashima, K. Sakurai, S. Baucheron, E. Giraud, B. Doublet, A. Cloeckaert, K. Nishino
  • Organizer: 8th Symposium on Antimicrobial Resistance in Animals and the Environment
  • Int'l Joint Research / Invited
• [Presentation] Bacterial adaptation to the gut environment: a constant fight against bile and drugs (2019)
  • Author(s): K. Nishino
  • Organizer: Taiwan-Japan Joint Seminar for biomedical informatics and engineering
  • Int'l Joint Research / Invited
• [Presentation] K. Nishino (2019)
  • Author(s): Antibiotic-Resistant Bacteria: Biggest Threats and Data
  • Organizer: The 1st AIRC-ISIR International Symposium
  • Int'l Joint Research / Invited
• [Presentation] K. Nishino (2019)
  • Author(s): Antibiotic-Resistant Bacteria: Biggest Threats and Data
  • Organizer: 8th imec Handai International Symposium
  • Int'l Joint Research / Invited
• [Remarks] researchmap
  • URL: https://researchmap.jp/read0210124
• [Remarks] 大阪大学産業科学研究所
  • URL: https://www.sanken.osaka-u.ac.jp
• [Remarks] 生体分子制御科学研究分野（西野研）
  • URL: https://www.sanken.osaka-u.ac.jp/organization/thi/thi_06/