A novel tricyclic β-lactam exhibiting potent antibacterial activities against carbapenem-resistant Enterobacterales: Synthesis and structure-activity-relationships

  • Bioorg Med Chem. 2021 Sep 15:46:116343. doi: 10.1016/j.bmc.2021.116343.
Jun Sato  1 ,  Hiroki Kusano  2 ,  Toshiaki Aoki  3 ,  Satoru Shibuya  2 ,  Katsuki Yokoo  2 ,  Kazuo Komano  2 ,  Takuya Oguma  2 ,  Shuhei Matsumoto  4 ,  Takafumi Sato  2 ,  Kazuya Yasuo  2 ,  Kenji Yamawaki  2
Affiliations
  • 1. Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka 561-0825, Japan. Electronic address: [email protected].
  • 2. Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka 561-0825, Japan.
  • 3. Shionogi CMC Research Innovation Center, Amagasaki-shi, Hyogo 660-0813, Japan.
  • 4. Head Office, 1-8, Doshomachi 3-chome, Chuo-ku, Osaka 541-0045, Japan.
PMID: 34450571 DOI: 10.1016/j.bmc.2021.116343
Abstract

A series of tricyclic β-lactams were synthesized and evaluated for in vitro Antibacterial activities against carbapenem-resistant Enterobacterales (CREs). Starting from a reported tricyclic β-lactam that combined the cephalosporin skeleton having a γ-lactone ring with a carboxylic acid group, which was reported as a unique partial structure of Lactivicin, we identified the compound which shows potent Antibacterial activities against all tested CREs by introducing sulfoxide. In addition, the sulfoxide-introduced tricyclic β-lactam also shows a strong therapeutic efficacy in the neutropenic mouse lung Infection model. These results indicate that the tricyclic β-lactam skeleton will show sufficient therapeutic performance in clinical use and therefore can serve as a scaffold in the search for new Antibacterial agents against CREs.

Keywords
Carbapenem-resistant Enterobacterale; Sulfoxide; Tricyclic β-lactam; β-lactam antibiotic; β-lactamase; γ-lactone.
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