Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA
Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA
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DOI：
10.1016/j.bmcl.2013.02.005
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发表时间：
2013-04-15
影响因子：
2.7
通讯作者：
Brown, Eric D.
中科院分区：
文献类型：
--
作者：
Barker, Courtney A.;Allison, Sarah E.;Brown, Eric D.
由于我们对细菌生理学的理解有限，而且我们对作用机制的认识也有限，因此，发现具有抗菌剂或细胞生物学探针功能的新型小分子受到了阻碍。我们先前采用化学基因组策略来鉴定一种新的小分子，MAC 13243，作为细菌脂蛋白靶向分子伴侣LolA的可能抑制剂。在这里，我们报告的降解MAC 13243的活性物种，S-（4-氯苄基）异噻唑烷。该化合物的类似物（例如，A22）先前已被表征为细菌肌动蛋白样蛋白MreB的抑制剂。在此，我们证明了MAC 13243和硫脲化合物的抗菌活性是相似的;这些活性分别响应于LolA拷贝数的增加或减少而被抑制或敏化。我们提供了STD NMR数据，其证实了LolA和MAC 13243的硫脲降解产物之间的物理相互作用，K-d类似于150 μ M。综上所述，我们得出结论，硫脲系列化合物具有相似的细胞机制，除了充分表征的靶MreB外，还包括与LolA的相互作用。(C)2013爱思唯尔有限公司保留所有权利。
The discovery of novel small molecules that function as antibacterial agents or cellular probes of biology is hindered by our limited understanding of bacterial physiology and our ability to assign mechanism of action. We previously employed a chemical genomic strategy to identify a novel small molecule, MAC13243, as a likely inhibitor of the bacterial lipoprotein targeting chaperone, LolA. Here, we report on the degradation of MAC13243 into the active species, S-(4-chlorobenzyl)isothiourea. Analogs of this compound (e.g., A22) have previously been characterized as inhibitors of the bacterial actin-like protein, MreB. Herein, we demonstrate that the antibacterial activity of MAC13243 and the thiourea compounds are similar; these activities are suppressed or sensitized in response to increases or decreases of LolA copy number, respectively. We provide STD NMR data which confirms a physical interaction between LolA and the thiourea degradation product of MAC13243, with a K-d of similar to 150 mu M. Taken together, we conclude that the thiourea series of compounds share a similar cellular mechanism that includes interaction with LolA in addition to the well-characterized target MreB. (C) 2013 Elsevier Ltd. All rights reserved.