Novel antimicrobial treatment of colistin-resistant bacteria

• Project/Area Number: 18K15158
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49050:Bacteriology-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Hirabayashi Aki 国立感染症研究所, 薬剤耐性研究センター, 主任研究官 (00801911)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: コリスチン / mcr / 外膜タンパク / 外膜タンパク質 / LPS / コリスチン耐性菌 / ドラッグリポジショニング / MCR

Outline of Final Research Achievements

Colistin is an antimicorobial drug used against multidrug-resistant Gram-negative bacteria. Recently, the colistin-resistant gene mcr has been detected via a transmissible plasmid, and it is urgent to establish a new treatment for infections caused by colistin-resistant bacteria.In this study, we screened a library of 780 drugs, including FDA-approved drugs, for 20 drugs that are effective in combination with low-dose colistin against colistin-resistant E. coli, and identified the extracellular membrane component protein X of Gram-negative bacteria as one of the candidate targets. It was suggested that the approved drugs bind to X and enhance the action of colistin by acting on the function of the outer membrane.

Academic Significance and Societal Importance of the Research Achievements

コリスチンは強力な殺菌作用をもつが、一方で量依存とされる腎毒性などの副作用の多い薬剤として知られている。コリスチン耐性菌による感染症の治療薬としてコリスチンのもつ殺菌作用を生かしつつ副作用の面からコリスチンの使用量を低減できる併用療法の開発は臨床現場において強く求められている。本研究はすでに他の目的で使用されている既承認薬の新しい作用点を見いだすことで既存薬の新規適用拡大や、より迅速な新たな治療法の開発につながり、臨床現場の課題の解決の一つとなりうる。

Research Products

• [Journal Article] On-Site Genomic Epidemiological Analysis of Antimicrobial-Resistant Bacteria in Cambodia With Portable Laboratory Equipment (2021)
  • Author(s): Hirabayashi Aki、Yanagisawa Hideji、Takahashi Hiromizu、Yahara Koji、Boeing Philipp、Wolfenden Bethan、Nov Vandarith、Lorn Vichet、Veng Mom、Ann Vuth、Darapheak Chau、Shibayama Keigo、Suzuki Masato
  • Journal Title: Frontiers in Microbiology Volume: 12 Pages: 675463-675463
  • DOI: 10.3389/fmicb.2021.675463
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasmid analysis of NDM metallo-β-lactamase-producing Enterobacterales isolated in Vietnam (2021)
  • Author(s): Hirabayashi Aki、Yahara Koji、Mitsuhashi Satomi、Nakagawa So、Imanishi Tadashi、Ha Van Thi Thu、Nguyen An Van、Nguyen Son Thai、Shibayama Keigo、Suzuki Masato
  • Journal Title: PLOS ONE Volume: 16 Issue: 7 Pages: e0231119-e0231119
  • DOI: 10.1371/journal.pone.0231119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Emergence of a plasmid-borne tigecycline resistance in Klebsiella pneumoniae in Vietnam (2021)
  • Author(s): Hirabayashi Aki、Ha Van Thi Thu、Nguyen An Van、Nguyen Son Thai、Shibayama Keigo、Suzuki Masato
  • Journal Title: Journal of Medical Microbiology Volume: 70 Issue: 3 Pages: 140-142
  • DOI: 10.1099/jmm.0.001320
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Transferable IncC-IncX3 Hybrid Plasmid Cocarrying <i>bla</i> _NDM-4 , <i>tet</i> (X), and <i>tmexCD3-toprJ3</i> Confers Resistance to Carbapenem and Tigecycline (2021)
  • Author(s): Hirabayashi Aki、Dao Trung Duc、Takemura Taichiro、Hasebe Futoshi、Trang Le Thi、Thanh Nguyen Ha、Tran Hoang Huy、Shibayama Keigo、Kasuga Ikuro、Suzuki Masato
  • Journal Title: mSphere Volume: 6 Issue: 4 Pages: 00592-21
  • DOI: 10.1128/msphere.00592-21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] コリスチン耐性菌に対する新規併用療法の開発 (2020)
  • Author(s): 平林亜希、柴山恵吾、鈴木仁人
  • Organizer: 日本細菌学会総会