Consequences of Depsipeptide Substitution on the CIpP Activation Activity of Antibacterial Acyldepsipeptides
Consequences of Depsipeptide Substitution on the CIpP Activation Activity of Antibacterial Acyldepsipeptides
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DOI：
10.1021/acsmedchemlett.7b00320
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发表时间：
2017-11-01
影响因子：
4.2
通讯作者：
Duerfeldt, Adam S.
中科院分区：
文献类型：
--
作者：
Li, Yangxiong;Lavey, Nathan P.;Duerfeldt, Adam S.
酰基缩肽（ADEP）抗生素通过临床上未开发的作用机制发挥作用，因此引起了多个抗菌开发小组的关注。 ADEP 支架在合成上易于处理，并且深层修饰已产生针对革兰氏阳性病原体的极其有效的抗菌先导化合物。尽管新鉴定的 ADEP 类似物对细菌分离株和细菌感染小鼠模型表现出显着的抗菌活性，但与缩酚肽核心相关的稳定性问题仍然存在。迄今为止，尚未有关于天然 ADEP 支架的研究报道评估大环连接对靶点参与、分子构象和生物活性的唯一重要性。为了解决 ADEP 结构-活性关系中的这一差距，我们合成了三种 ADEP 类似物，它们仅在连接基序上有所不同（即酯、酰胺和 N-甲基酰胺），并提供构象行为和生物活性的并排比较。我们证明，虽然用仲酰胺取代天然存在的酯键可以保持体外生化活性，但这种简单的取代会导致全细胞活性显着下降。这项研究提供了直接证据，表明酯到酰胺键的取代解决了 ADEP 的不稳定性。
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 demonstrate that while replacement of the naturally occurring ester linkage with a secondary amide maintains in vitro biochemical activity, this simple substitution results in a significant drop in whole-cell activity. This study provides direct evidence that ester to amide linkage substitution solution for ADEP instability.