Mode of action study of a novel antituberculous agent CPZEN-45

• Project/Area Number: 26870829
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Bacteriology (including mycology); Applied biochemistry
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: ISHIZAKI Yoshimasa 公益財団法人微生物化学研究会, 微生物化学研究所, 主任研究員 (10414103)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 作用機序の同定 / CPZEN－45 / 新規抗結核薬 / WecA / arabinogalactan ligase / WecA阻害 / アラビノガラクタン生合成

Outline of Final Research Achievements

In this research, I tried to identify the primary target of CPZEN-45, which is a promising anti tubercular agent derivatized from natural product caprazamycins. At the beginning of this research, I focused on following three candidate enzymes for the target; (1) MurX which is a target of caprazamycins and involved in peptidoglycan biosynthesis, (2) WecA which is a paralog of MurX and involved in biosynthesis of arabinogalactan (AG), and (3) AG ligase, which has similar function to MurX and WecA.
As the result of this research, it is revealed that CPZEN-45 inhibited the activity of WecA and de novo synthesis of AG. In contrast, CPZEN-45 did not inhibit the activity of MurX, which is a primary target of caprazamycins. These results indicated that CPZEN-45 showed antituberculous activity by inhibiting WecA enzyme and subsequent blocking of AG biosynthesis.
Also, my collaborator and I succeeded to identify AG ligase, which we expected to be a candidate of target of CPZEN-45.

Research Products

• [Int'l Joint Research] コロラド州立大学(米国)
• [Presentation] CPZEN-45; a promising drug candidate for treating extremely drug-resistant tuberculosis (XDR-TB): synthesis, activity, and mode of action (2016)
  • Author(s): Yoshimasa Ishizaki, Kazushige Sasaki, Yoshiaki Takahashi, Masayuki Igarashi, Toshiaki Miyake, Masaji Okada, Norio Doi, Patrick J. Brennan, Yuzuru Akamatsu, Akio Nomoto, and Masakatsu Shibasaki
  • Organizer: 2016 Colorado Mycobacteria Conference
  • Place of Presentation: アメリカ合衆国、コロラド州
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] CPZEN-45, As a Promising Drug Candidate for Treating Extremely Drug-Resistant Tuberculosis (XDR-TB): Synthesis, Activity and Mode of Action (2015)
  • Author(s): Kazushige Sasaki, Yoshimasa Ishizaki, Yoshiaki Takahashi, Masayuki Igarashi, Toshiaki Miyake, Masaji Okada, Norio Doi, Patrick J. Brennan, Yuzuru Akamatsu, Akio Nomoto
  • Organizer: International Symposium for Medicinal Sciences（日本薬学会第135年会）
  • Place of Presentation: 兵庫医療大学 オクタホール（神戸）
  • Year and Date: 2015-03-27
• [Presentation] A Semisynthetic Antitubercular Agent CPZEN-45 Inhibits the GlcNAc-1-phosphate Transferase WecA, Involved in Mycobacterial Arabinogalactan Biosynthesis (2014)
  • Author(s): Yoshimasa Ishizaki, Venugopal Pujari, Chigusa Hayashi, Kunio Inoue, Masayuki Igarashi, Yoshiaki Takahashi, Dean C. Crick, Patrick J. Brennan, Akio Nomoto
  • Organizer: 54th Interscience Conference on Antimicrobial Agents and Chemotherapy
  • Place of Presentation: Walter E. Washington convention center（米国）
  • Year and Date: 2014-09-09