Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria.
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| Main Authors: | , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
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European journal of medicinal chemistry
2025
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| _version_ | 1868266255346040832 |
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| author | Liu, Wandong Guo, Yan Zhang, Chen Liu, Chenyu Chen, Sheng Li, Xiaoyang Qiu, Jiazhang Wan, Shengbiao |
| author_facet | Liu, Wandong Guo, Yan Zhang, Chen Liu, Chenyu Chen, Sheng Li, Xiaoyang Qiu, Jiazhang Wan, Shengbiao Liu, Wandong Guo, Yan Zhang, Chen Liu, Chenyu Chen, Sheng Li, Xiaoyang Qiu, Jiazhang Wan, Shengbiao |
| collection | PubMed - marine biology |
| contents | Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria. Liu, Wandong Guo, Yan Zhang, Chen Liu, Chenyu Chen, Sheng Li, Xiaoyang Qiu, Jiazhang Wan, Shengbiao beta-Lactamases Anti-Bacterial Agents Microbial Sensitivity Tests Meropenem Animals Structure-Activity Relationship Mice Molecular Structure Dose-Response Relationship, Drug Drug Resistance, Bacterial Escherichia coli beta-Lactamase Inhibitors Organoselenium Compounds Isoindoles The emergence of New Delhi metallo-β-lactamase-1 (NDM-1) poses a significant threat to the clinical application of antibiotics, as it possesses the ability to hydrolyze nearly all β-lactam antibiotics. Regrettably, there are currently no clinical drugs targeting NDM-1, making it imperative to develop highly potent and minimally toxic NDM-1 inhibitors. Herein, a series of molecular Trojan horses targeting NDM-1 were synthesized by introducing ebselen into 7-aminocephalosporanic acid derivatives via a C-Se bond. Representative compound 18b exhibited potent inhibitory activity against NDM-1, with an IC value of 7.03 μM, and combining with meropenem (Mem) decreased the minimum inhibitory concentration (MIC) of Mem by 4-32-fold in NDM-1 expressing bacteria. Mechanistically, 18b released the ebselen moiety at the active site of NDM-1, forming a Se-S bond with Cys208 to achieve targeted drug delivery of ebselen. Importantly, 18b demonstrated potent inhibition of resistant bacterial growth and replication in mice when administered in combination with Mem. These results suggest that 18b is a promising candidate for treating infections caused by resistant bacteria expressing NDM-1. |
| format | Artículo científico |
| id | pubmed_39798399 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | European journal of medicinal chemistry |
| record_format | pubmed |
| spellingShingle | Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria. Liu, Wandong Guo, Yan Zhang, Chen Liu, Chenyu Chen, Sheng Li, Xiaoyang Qiu, Jiazhang Wan, Shengbiao beta-Lactamases Anti-Bacterial Agents Microbial Sensitivity Tests Meropenem Animals Structure-Activity Relationship Mice Molecular Structure Dose-Response Relationship, Drug Drug Resistance, Bacterial Escherichia coli beta-Lactamase Inhibitors Organoselenium Compounds Isoindoles Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria. Liu, Wandong Guo, Yan Zhang, Chen Liu, Chenyu Chen, Sheng Li, Xiaoyang Qiu, Jiazhang Wan, Shengbiao beta-Lactamases Anti-Bacterial Agents Microbial Sensitivity Tests Meropenem Animals Structure-Activity Relationship Mice Molecular Structure Dose-Response Relationship, Drug Drug Resistance, Bacterial Escherichia coli beta-Lactamase Inhibitors Organoselenium Compounds Isoindoles The emergence of New Delhi metallo-β-lactamase-1 (NDM-1) poses a significant threat to the clinical application of antibiotics, as it possesses the ability to hydrolyze nearly all β-lactam antibiotics. Regrettably, there are currently no clinical drugs targeting NDM-1, making it imperative to develop highly potent and minimally toxic NDM-1 inhibitors. Herein, a series of molecular Trojan horses targeting NDM-1 were synthesized by introducing ebselen into 7-aminocephalosporanic acid derivatives via a C-Se bond. Representative compound 18b exhibited potent inhibitory activity against NDM-1, with an IC value of 7.03 μM, and combining with meropenem (Mem) decreased the minimum inhibitory concentration (MIC) of Mem by 4-32-fold in NDM-1 expressing bacteria. Mechanistically, 18b released the ebselen moiety at the active site of NDM-1, forming a Se-S bond with Cys208 to achieve targeted drug delivery of ebselen. Importantly, 18b demonstrated potent inhibition of resistant bacterial growth and replication in mice when administered in combination with Mem. These results suggest that 18b is a promising candidate for treating infections caused by resistant bacteria expressing NDM-1. |
| title | Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria. |
| topic | beta-Lactamases Anti-Bacterial Agents Microbial Sensitivity Tests Meropenem Animals Structure-Activity Relationship Mice Molecular Structure Dose-Response Relationship, Drug Drug Resistance, Bacterial Escherichia coli beta-Lactamase Inhibitors Organoselenium Compounds Isoindoles |
| url | https://pubmed.ncbi.nlm.nih.gov/39798399/ |