Journal
ACS INFECTIOUS DISEASES
Volume 8, Issue 3, Pages 400-410Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.1c00549
Keywords
beta-lactam antibiotic; tricyclic beta-lactam; carbapenem-resistant Enterobacterale; porin deficiency; penicillin-binding protein 3
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Funding
- Shionogi Techno Advance Research Co., Ltd.
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The emergence of carbapenem-resistant enterobacterales (CREs) is a significant global clinical and public health threat. This study reports the discovery of a potent tricyclic beta-lactam compound that overcomes resistance mechanisms other than beta-lactamase production. The compound showed promising therapeutic efficacy in a mouse lung infection model, making it a potential drug candidate for infectious diseases caused by CREs.
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 beta-lactam skeleton which exhibits potent antibacterial activities against several problematic beta-lactamase-producing CREs without a beta-lactamase inhibitor, we found that these activities were reduced against clinical isolates with resistance mechanisms other than beta-lactamase production. These mechanisms were the reduction of outer membrane permeability with the production of beta-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 beta-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.
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