The New Delhi Metallo-β-lactamase-1 Covalent Inhibitors Derived from Cephalexin Effectively Reverse Meropenem Resistance.
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| Autores principales: | , , , , , , , , , |
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| Formato: | Artículo científico |
| Lenguaje: | en |
| Publicado: |
Journal of medicinal chemistry
2026
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| _version_ | 1868266048916029440 |
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| author | Liu, Wandong Liu, Chenyu Guo, Yan Liu, Zhiying Zhang, Chen Meng, Wanli Wan, Shengbiao Chen, Sheng Qiu, Jiazhang Yu, Rilei |
| author_facet | Liu, Wandong Liu, Chenyu Guo, Yan Liu, Zhiying Zhang, Chen Meng, Wanli Wan, Shengbiao Chen, Sheng Qiu, Jiazhang Yu, Rilei Liu, Wandong Liu, Chenyu Guo, Yan Liu, Zhiying Zhang, Chen Meng, Wanli Wan, Shengbiao Chen, Sheng Qiu, Jiazhang Yu, Rilei |
| collection | PubMed - marine biology |
| contents | The New Delhi Metallo-β-lactamase-1 Covalent Inhibitors Derived from Cephalexin Effectively Reverse Meropenem Resistance. Liu, Wandong Liu, Chenyu Guo, Yan Liu, Zhiying Zhang, Chen Meng, Wanli Wan, Shengbiao Chen, Sheng Qiu, Jiazhang Yu, Rilei beta-Lactamase Inhibitors Meropenem beta-Lactamases Animals Anti-Bacterial Agents Mice Microbial Sensitivity Tests Cephalexin Structure-Activity Relationship New Delhi metallo-β-lactamase-1 (NDM-1) hydrolyzes carbapenems and most β-lactam antibiotics, posing a significant threat to global health and underscoring the urgent need for effective inhibitors. To address this unmet need, we designed a series of covalent NDM-1 inhibitors by introducing a selenazolone warhead into the cephalexin scaffold. Among them, compound demonstrated the most potent inhibitory activity, with an IC value of 3.27 μM. The combination of and meropenem (Mem) synergistically lowered the MIC of Mem 8-16-fold in NDM-1-positive isolates and potently suppressed NDM-1-positive bacterial growth in a mouse infection model. Mechanistically, forms a stable Se-S bond with Cys208 at the NDM-1 active site through its selenazolone warhead, enabling prolonged target engagement and sustained enzyme inhibition. Collectively, these findings demonstrate that covalent inhibitors derived from the cephalexin scaffold represent a promising strategy for combating NDM-1-mediated resistance, offering valuable leads for targeting metallo-β-lactamases. |
| format | Artículo científico |
| id | pubmed_42138890 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Journal of medicinal chemistry |
| record_format | pubmed |
| spellingShingle | The New Delhi Metallo-β-lactamase-1 Covalent Inhibitors Derived from Cephalexin Effectively Reverse Meropenem Resistance. Liu, Wandong Liu, Chenyu Guo, Yan Liu, Zhiying Zhang, Chen Meng, Wanli Wan, Shengbiao Chen, Sheng Qiu, Jiazhang Yu, Rilei beta-Lactamase Inhibitors Meropenem beta-Lactamases Animals Anti-Bacterial Agents Mice Microbial Sensitivity Tests Cephalexin Structure-Activity Relationship The New Delhi Metallo-β-lactamase-1 Covalent Inhibitors Derived from Cephalexin Effectively Reverse Meropenem Resistance. Liu, Wandong Liu, Chenyu Guo, Yan Liu, Zhiying Zhang, Chen Meng, Wanli Wan, Shengbiao Chen, Sheng Qiu, Jiazhang Yu, Rilei beta-Lactamase Inhibitors Meropenem beta-Lactamases Animals Anti-Bacterial Agents Mice Microbial Sensitivity Tests Cephalexin Structure-Activity Relationship New Delhi metallo-β-lactamase-1 (NDM-1) hydrolyzes carbapenems and most β-lactam antibiotics, posing a significant threat to global health and underscoring the urgent need for effective inhibitors. To address this unmet need, we designed a series of covalent NDM-1 inhibitors by introducing a selenazolone warhead into the cephalexin scaffold. Among them, compound demonstrated the most potent inhibitory activity, with an IC value of 3.27 μM. The combination of and meropenem (Mem) synergistically lowered the MIC of Mem 8-16-fold in NDM-1-positive isolates and potently suppressed NDM-1-positive bacterial growth in a mouse infection model. Mechanistically, forms a stable Se-S bond with Cys208 at the NDM-1 active site through its selenazolone warhead, enabling prolonged target engagement and sustained enzyme inhibition. Collectively, these findings demonstrate that covalent inhibitors derived from the cephalexin scaffold represent a promising strategy for combating NDM-1-mediated resistance, offering valuable leads for targeting metallo-β-lactamases. |
| title | The New Delhi Metallo-β-lactamase-1 Covalent Inhibitors Derived from Cephalexin Effectively Reverse Meropenem Resistance. |
| topic | beta-Lactamase Inhibitors Meropenem beta-Lactamases Animals Anti-Bacterial Agents Mice Microbial Sensitivity Tests Cephalexin Structure-Activity Relationship |
| url | https://pubmed.ncbi.nlm.nih.gov/42138890/ |