Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors
| Autor: | Yang Lingling, Zhenling Wang, Ji Deng, Kai-Rong Zhu, Chao Li, Guo-Bo Li, Wenfang Li, Qing-Qing Dai, Yu-Hang Yan, Wei Chen |
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| Rok vydání: | 2021 |
| Předmět: |
Carboxylic Acids
Microbial Sensitivity Tests medicine.disease_cause Meropenem beta-Lactamases Rats Sprague-Dawley Mice Structure-Activity Relationship In vivo Drug Discovery polycyclic compounds medicine Escherichia coli Animals Humans Tissue Distribution Pharmacology Mice Inbred ICR biology Dose-Response Relationship Drug Molecular Structure Pseudomonas aeruginosa Chemistry Organic Chemistry Imidazoles Active site General Medicine biochemical phenomena metabolism and nutrition bacterial infections and mycoses biology.organism_classification Anti-Bacterial Agents Rats Biochemistry biology.protein Female Antibacterial activity Bacterial outer membrane beta-Lactamase Inhibitors Bacteria medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 228 |
| ISSN: | 1768-3254 |
| Popis: | Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the ‘last-resort’ carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed most potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance. |
| Databáze: | OpenAIRE |
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