Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides
| Autor: | Jessica E. Knobbe, Yu-Shan Lin, Jesse A. Coker, Yangxiong Li, Adam S. Duerfeldt, Hongtao Yu, Susan L. Nimmo, Dat C. Truong, Nathan P. Lavey |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Depsipeptide Stereochemistry Organic Chemistry Target engagement Biological activity Biology 010402 general chemistry 01 natural sciences Biochemistry Molecular conformation 0104 chemical sciences 03 medical and health sciences 030104 developmental biology Mechanism of action Drug Discovery medicine medicine.symptom Antibacterial activity |
| Zdroj: | ACS medicinal chemistry letters. 8(11) |
| ISSN: | 1948-5875 |
| Popis: | The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gram-positive pathogens. Although newly identified ADEP analogs demonstrate remarkable antibacterial activity against bacterial isolates and in mouse models of bacterial infections, stability issues pertaining to the depsipeptide core remain. To date, no study has been reported on the natural ADEP scaffold that evaluates the sole importance of the macrocyclic linkage on target engagement, molecular conformation, and bioactivity. To address this gap in ADEP structure–activity relationships, we synthesized three ADEP analogs that only differ in the linkage motif (i.e., ester, amide, and N-methyl amide) and provide a side-by-side comparison of conformational behavior and biological activity. We de... |
| Databáze: | OpenAIRE |
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