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| Main Authors: | , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Journal of medicinal chemistry
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41229169/ |
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| _version_ | 1868266127729098754 |
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| author | Guo, Yan Liu, Chenyu Liu, Wandong Zhang, Chen Liu, Zhiying Wan, Shengbiao Xu, Ximing Chen, Sheng Qiu, Jiazhang |
| author_facet | Guo, Yan Liu, Chenyu Liu, Wandong Zhang, Chen Liu, Zhiying Wan, Shengbiao Xu, Ximing Chen, Sheng Qiu, Jiazhang Guo, Yan Liu, Chenyu Liu, Wandong Zhang, Chen Liu, Zhiying Wan, Shengbiao Xu, Ximing Chen, Sheng Qiu, Jiazhang |
| collection | PubMed - marine biology |
| contents | Structure-Directed Optimization of Ebselen Derivatives as Potent NDM-1 Inhibitors Reverses Meropenem Resistance. Guo, Yan Liu, Chenyu Liu, Wandong Zhang, Chen Liu, Zhiying Wan, Shengbiao Xu, Ximing Chen, Sheng Qiu, Jiazhang Isoindoles beta-Lactamases Organoselenium Compounds Microbial Sensitivity Tests Animals beta-Lactamase Inhibitors Structure-Activity Relationship Meropenem Azoles Anti-Bacterial Agents Mice Humans Drug Resistance, Bacterial Escherichia coli "Superbugs" harboring the New Delhi metallo-β-lactamase-1 (NDM-1) have disseminated globally, posing a severe threat to the clinical efficacy of β-lactam antibiotics. Developing NDM-1 inhibitors to restore the efficacy of β-lactam antibiotics against resistant bacteria is critically important. Using ebselen as a lead, we designed and synthesized 59 novel derivatives to develop potent NDM-1 inhibitors. Among them, compound demonstrated the most potent NDM-1 inhibitory activity with an IC value of 1.12 μM. The combination of and Mem reduced the minimum inhibitory concentration (MIC) of Mem by 4-16-fold in NDM-1-producing isolates. Importantly, the combination of and Mem effectively suppressed the bacterial loads in mice. Mechanistically, effectively inhibits the activity of NDM-1 by forming a Se-S covalent bond with the NDM-1 protein. Collectively, these findings confirm that compound is an excellent NDM-1 covalent inhibitor, offering a promising lead compound for addressing bacterial resistance driven by NDM-1. |
| format | Artículo científico |
| id | pubmed_41229169 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Journal of medicinal chemistry |
| record_format | pubmed |
| spellingShingle | Structure-Directed Optimization of Ebselen Derivatives as Potent NDM-1 Inhibitors Reverses Meropenem Resistance. Guo, Yan Liu, Chenyu Liu, Wandong Zhang, Chen Liu, Zhiying Wan, Shengbiao Xu, Ximing Chen, Sheng Qiu, Jiazhang Isoindoles beta-Lactamases Organoselenium Compounds Microbial Sensitivity Tests Animals beta-Lactamase Inhibitors Structure-Activity Relationship Meropenem Azoles Anti-Bacterial Agents Mice Humans Drug Resistance, Bacterial Escherichia coli Structure-Directed Optimization of Ebselen Derivatives as Potent NDM-1 Inhibitors Reverses Meropenem Resistance. Guo, Yan Liu, Chenyu Liu, Wandong Zhang, Chen Liu, Zhiying Wan, Shengbiao Xu, Ximing Chen, Sheng Qiu, Jiazhang Isoindoles beta-Lactamases Organoselenium Compounds Microbial Sensitivity Tests Animals beta-Lactamase Inhibitors Structure-Activity Relationship Meropenem Azoles Anti-Bacterial Agents Mice Humans Drug Resistance, Bacterial Escherichia coli "Superbugs" harboring the New Delhi metallo-β-lactamase-1 (NDM-1) have disseminated globally, posing a severe threat to the clinical efficacy of β-lactam antibiotics. Developing NDM-1 inhibitors to restore the efficacy of β-lactam antibiotics against resistant bacteria is critically important. Using ebselen as a lead, we designed and synthesized 59 novel derivatives to develop potent NDM-1 inhibitors. Among them, compound demonstrated the most potent NDM-1 inhibitory activity with an IC value of 1.12 μM. The combination of and Mem reduced the minimum inhibitory concentration (MIC) of Mem by 4-16-fold in NDM-1-producing isolates. Importantly, the combination of and Mem effectively suppressed the bacterial loads in mice. Mechanistically, effectively inhibits the activity of NDM-1 by forming a Se-S covalent bond with the NDM-1 protein. Collectively, these findings confirm that compound is an excellent NDM-1 covalent inhibitor, offering a promising lead compound for addressing bacterial resistance driven by NDM-1. |
| title | Structure-Directed Optimization of Ebselen Derivatives as Potent NDM-1 Inhibitors Reverses Meropenem Resistance. |
| topic | Isoindoles beta-Lactamases Organoselenium Compounds Microbial Sensitivity Tests Animals beta-Lactamase Inhibitors Structure-Activity Relationship Meropenem Azoles Anti-Bacterial Agents Mice Humans Drug Resistance, Bacterial Escherichia coli |
| url | https://pubmed.ncbi.nlm.nih.gov/41229169/ |