Design, Synthesis, and Biological Evaluation of Novel Arylomycins against Multidrug-Resistant Gram-Negative Bacteria
G0775, an arylomycin-type SPase I inhibitor that is being evaluated in a preclinical study, exhibited potent antibacterial activities against some Gram-negative bacteria but meanwhile suffered defects such as a narrow antibacterial spectrum and poor pharmacokinetic properties. Herein, systematic structural modifications were carried out, including optimization of the macrocyclic skeleton, warheads, and lipophilic regions. The optimization culminated in the discovery of 138f, which showed more potent activity and a broader spectrum against clinically isolated carbapenem-resistant Gram-negative bacteria, especially against Acinetobacter baumannii and Pseudomonas aeruginosa. 162, the free amine of 138f, exhibited an excellent pharmacokinetic profile in rats. In a neutropenic mouse thigh model of infection with multidrug-resistant P. aeruginosa, the potent in vivo antibacterial efficacy of 162 was confirmed and superior to that of G0775 (3.5-log decrease vs 1.1-log decrease in colony-forming unit (CFU)). These results support 162 as a potential antimicrobial agent for further research.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
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| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 8 vom: 25. Apr., Seite 6585-6609 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Yinyong [VerfasserIn] |
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| Links: |
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| Themen: |
Anti-Bacterial Agents |
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| Anmerkungen: |
Date Completed 25.04.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.4c00018 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370876962 |
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| 520 | |a G0775, an arylomycin-type SPase I inhibitor that is being evaluated in a preclinical study, exhibited potent antibacterial activities against some Gram-negative bacteria but meanwhile suffered defects such as a narrow antibacterial spectrum and poor pharmacokinetic properties. Herein, systematic structural modifications were carried out, including optimization of the macrocyclic skeleton, warheads, and lipophilic regions. The optimization culminated in the discovery of 138f, which showed more potent activity and a broader spectrum against clinically isolated carbapenem-resistant Gram-negative bacteria, especially against Acinetobacter baumannii and Pseudomonas aeruginosa. 162, the free amine of 138f, exhibited an excellent pharmacokinetic profile in rats. In a neutropenic mouse thigh model of infection with multidrug-resistant P. aeruginosa, the potent in vivo antibacterial efficacy of 162 was confirmed and superior to that of G0775 (3.5-log decrease vs 1.1-log decrease in colony-forming unit (CFU)). These results support 162 as a potential antimicrobial agent for further research | ||
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| 700 | 1 | |a Zhang, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Wenhao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hongyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Zhengyu |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xianli |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yushe |e verfasserin |4 aut | |
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