Optimization of globomycin analogs as novel gram-negative antibiotics
| Autor: | Keira Garland, Richard Pastor, Gauri Deshmukh, Min Xu, Emily J. Hanan, Paul Gibbons, Yi-Chen Chen, Susan L. Gloor, Sharookh B. Kapadia, Homer Pantua, Sharada Labadie, Rongbao Hua, Yiming Xu, Marie-Gabrielle Braun, Yuhong Fu, Craig Stivala, Xiongcai Liu, Georgette Castanedo, Jonathan Cheong, Daniels Blake, Hao Zheng, Daniel J. Burdick, Yun-Xing Cheng |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.drug_class
Clinical Biochemistry Antibiotics Pharmaceutical Science Microbial Sensitivity Tests Lipoprotein signal peptidase 01 natural sciences Biochemistry Unmet needs chemistry.chemical_compound Structure-Activity Relationship In vivo Drug Discovery medicine Escherichia coli Molecular Biology Gram Depsipeptide Signal peptidase Natural product Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry 0104 chemical sciences Anti-Bacterial Agents 010404 medicinal & biomolecular chemistry Molecular Medicine Peptides |
| Zdroj: | Bioorganicmedicinal chemistry letters. 30(20) |
| ISSN: | 1464-3405 |
| Popis: | Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 μM) and 61 (E. coli MIC 0.78 μM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery. |
| Databáze: | OpenAIRE |
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