1. Academic Validation
  2. Discovery of a Tricyclic β-Lactam as a Potent Antimicrobial Agent against Carbapenem-Resistant Enterobacterales, Including Strains with Reduced Membrane Permeability and Four-Amino Acid Insertion into Penicillin-Binding Protein 3: Structure-Activity-Relationships and In Vitro and In Vivo Activities

Discovery of a Tricyclic β-Lactam as a Potent Antimicrobial Agent against Carbapenem-Resistant Enterobacterales, Including Strains with Reduced Membrane Permeability and Four-Amino Acid Insertion into Penicillin-Binding Protein 3: Structure-Activity-Relationships and In Vitro and In Vivo Activities

  • ACS Infect Dis. 2022 Mar 11;8(3):400-410. doi: 10.1021/acsinfecdis.1c00549.
Jun Sato 1 Hiroki Kusano 1 Toshiaki Aoki 2 Satoru Shibuya 1 Katsuki Yokoo 1 Kazuo Komano 1 Takuya Oguma 1 Shuhei Matsumoto 3 Rio Nakamura 4 Takafumi Sato 1 Kenji Yamawaki 1
Affiliations

Affiliations

  • 1 Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka 561-0825, Japan.
  • 2 Shionogi CMC Research Innovation Center, Amagasaki-shi, Hyogo 660-0813, Japan.
  • 3 Shionogi, Head Office, 1-8, Doshomachi 3-chome, Chuo-ku, Osaka 541-0045, Japan.
  • 4 Shionogi TechnoAdvance Research Co., Ltd., Toyonaka-shi, Osaka 561-0825, Japan.
Abstract

The current worldwide emergence of carbapenem-resistant enterobacterales (CREs) constitutes an important growing clinical and public health threat. Acquired carbapenemases are the most important determinants of resistance to carbapenems. In the development of the previously reported tricyclic β-lactam skeleton which exhibits potent Antibacterial activities against several problematic β-lactamase-producing CREs without a β-lactamase inhibitor, we found that these activities were reduced against clinical isolates with resistance mechanisms other than β-lactamase production. These mechanisms were the reduction of outer membrane permeability with the production of β-lactamases and the insertion of four Amino acids into penicillin-binding protein 3. Here, we report the discovery of a potent compound that overcomes these resistance mechanisms by the conversion of the alkoxyimino moiety of the aminothiazole side chain in which a hydrophilic functional group is introduced and the carboxylic acid of the alkoxyimino moiety is converted to reduce the negative charge of the whole molecule from 2 to 1. This potent tricyclic β-lactam is a promising drug candidate for infectious diseases caused by CREs due to its potent therapeutic efficacy in the neutropenic mouse lung Infection model and low frequency of producing spontaneously resistant mutants.

Keywords

carbapenem-resistant Enterobacterale; penicillin-binding protein 3; porin deficiency; tricyclic β-lactam; β-lactam antibiotic.

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