Introduction of a Thio Functional Group to Diazabicyclooctane: An Effective Modification to Potentiate the Activity of β-Lactams against Gram-Negative Bacteria Producing Class A, C, and D Serine β-Lactamases
| Autor: | Motohiro Fujiu, Tomoyuki Kawachi, Jun Sato, Kazuo Komano, Satoshi Miyagawa, Katsuki Yokoo, Satoru Shibuya, Kenji Yamawaki, Soichiro Sato, Hiroki Kusano, Naoki Kohira, Toshiaki Aoki |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Gram-negative bacteria biology Chemistry β lactamases 030106 microbiology Thio Microbial Sensitivity Tests beta-Lactams biology.organism_classification beta-Lactamases Anti-Bacterial Agents Microbiology Serine 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Infectious Diseases β lactamase inhibitor Gram-Negative Bacteria β lactams Functional group Bacteria |
| Zdroj: | ACS Infectious Diseases. 6:3034-3047 |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.0c00560 |
| Popis: | By the emergence and worldwide spread of multi-drug-resistant Gram-negative bacteria, there have been growing demands for efficacious drugs to cure these resistant infections. The key mechanism for resistance to β-lactam antibiotics is the production of β-lactamases, which hydrolyze and deactivate β-lactams. Diazabicyclooctane (DBO) analogs play an important role as one of the new classes of β-lactamase inhibitors (BLIs), and several compounds such as avibactam (AVI) have been approved by the FDA, along with many derivatives under clinical or preclinical development. Although these compounds have a similar amide substituent at the C2 position, we have recently reported the synthesis of novel DBO analogs which possess a thio functional group. This structural modification enhances the ability to restore the antimicrobial activities of cefixime (CMF) against pathogens producing classes A, C, and D serine β-lactamases compared with AVI and expands the structural tolerance at the six position. Furthermore, some of these analogs showed intrinsic microbial activities based on multipenicillin binding protein (PBP) inhibition. This is the unique feature which has never been observed in DBOs. One of our DBOs had a pharmacokinetic profile comparable to that of other DBOs. These results indicate that the introduction of a thio functional group into DBO is a novel and effective modification to discover a clinically useful new BLI. |
| Databáze: | OpenAIRE |
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