Development of atomic structural platform for controlling multi-drug resistant bacteria

• Project/Area Number: 15H05672
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Infectious disease medicine
• Research Institution: Nagoya University
• Principal Investigator: Wachino Jun-ichi 名古屋大学, 医学系研究科, 講師 (00535651)
• Research Collaborator: KANECHI Leo 名古屋大学, 大学院医学系研究科 ; KANAYAMA Takato 名古屋大学, 大学院医学系研究科
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
• Keywords: 薬剤耐性菌 / メタロベータラクタマーゼ / 16S rRNA メチルトランスフェラーゼ / 阻害剤 / メタロβ-ラクタマーゼ / ニトロセフィン / セフタジジム / メロペネム / ハイスループット / 薬剤耐性 / 16S rRNA MTase / in silico screening / 蛋白結晶

Outline of Final Research Achievements

Emergence of multidrug-resistant bacteria is becoming a major clinical threat. To overcome the problem of multidrug-resistant bacteria, it needs to develop new antibacterial agents and treatment. In this study, we aimed to develop new agents targeting for antibiotic resistance proteins produced in bacteria. Inhibition of antibiotic resistance mechanism by chemical compounds is expected to revive the efficacy of already-existing antibiotics. We targeted metallo-beta-lactamases and 16S rRNA methyltransferases, which are involved in carbapenem and aminoglycoside resistance, respectively. we screened for chemical compounds using in silico and in vitro techniques and identified several inhibitor candidates of metallo-beta-lactamases and 16S rRNA methyltransferases.

Research Products

• [Journal Article] Structural Insights into the TLA-3 Extended-Spectrum β-Lactamase and Its Inhibition by Avibactam and OP0595 (2017)
  • Author(s): Jin W, Wachino JI, Yamaguchi Y, Kimura K, Kumar A, Yamada M, Morinaka A, Sakamaki Y, Yonezawa M, Kurosaki H, Arakawa Y
  • Journal Title: Antimicrob Agents Chemother Volume: 61
  • Peer Reviewed
• [Journal Article] Specific blaCTX-M-8/IncI1 Plasmid Transfer among Genetically Diverse Escherichia coli Isolates between Humans and Chickens (2017)
  • Author(s): Norizuki C, Wachino JI, Suzuki M, Kawamura K, Nagano N, Kimura K, Arakawa Y.
  • Journal Title: Antimicrob Agents Chemother Volume: 61
• [Journal Article] Structural Insights into Recognition of Hydrolyzed Carbapenems and Inhibitors by Subclass B3 Metallo-β-Lactamase SMB-1 (2016)
  • Author(s): Wachino J, Yamaguchi Y, Mori S, Jin W, Kimura K, Kurosaki H, Arakawa Y.
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 60 Issue: 7 Pages: 4274-4282
  • DOI: 10.1128/aac.03108-15
  • Peer Reviewed / Acknowledgement Compliant