Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics.
Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics.
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DOI：
10.1002/cmdc.201700793
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发表时间：
2018-04-23
期刊：
影响因子：
3.4
通讯作者：
Ducho C
中科院分区：
文献类型：
--
作者：
Koppermann S;Cui Z;Fischer PD;Wang X;Ludwig J;Thorson JS;Van Lanen SG;Ducho C
Muraymycins是具有抗菌活性的尿苷衍生天然产物的一个亚类。已经报道了几种村霉素类似物的生物学数据，包括对其靶蛋白（细菌膜酶MraY）的一些体外抑制活性。然而，迄今为止，基于这种体外数据的天然存在的muraymycins的结构-活性关系（SAR）研究一直缺失。在这项工作中，我们报告了一个详细的SAR调查的代表四个村霉素亚组A-D使用基于荧光的体外MraY测定。对于一些muraymycins，观察到MraY的抑制，IC 50值在低pM范围内。这些抑制效力与抗菌活性进行了比较，并与来自先前报道的X-射线晶体结构的MraY与村霉素抑制剂复合的建模数据相关。总体而言，这些结果将为开发具有优化性质的村霉素类似物作为抗菌药物候选物铺平道路。研究了天然存在的Muraymycin核苷抗生素对其靶蛋白细菌膜酶MraY的抑制活性。体外MraY测定提供了几种代表性的穆雷霉素的SAR数据。这些抑制效力相关的抗菌活性和建模数据，从而提供了详细的见解的目标相互作用的muraymycins。
Muraymycins are a subclass of antimicrobially active uridine-derived natural products. Biological data on several muraymycin analogues have already been reported, including some inhibitory in vitro activities towards their target protein, the bacterial membrane enzyme MraY. However, a structure-activity relationship (SAR) study on naturally occurring muraymycins based on such in vitro data has been missing so far. In this work, we report a detailed SAR investigation on representatives of the four muraymycin subgroups A–D using a fluorescence-based in vitro MraY assay. For some muraymycins, inhibition of MraY with IC50 values in the low pM range was observed. These inhibitory potencies were compared with antibacterial activities and were correlated to modelling data derived from a previously reported X-ray crystal structure of MraY in complex with a muraymycin inhibitor. Overall, these results will pave the way for the development of muraymycin analogues with optimized properties as antibacterial drug candidates. Naturally occurring muraymycin nucleoside antibiotics were studied for inhibitory activities towards their target protein, the bacterial membrane enzyme MraY. An in vitro MraY assay furnished SAR data on several representative muraymycins. These inhibitory potencies were correlated to antibacterial activities and to modelling data, thus providing detailed insights into the target interaction of muraymycins.
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DOI：
10.1126/science.1236501
发表时间：
2013-08-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung BC;Zhao J;Gillespie RA;Kwon DY;Guan Z;Hong J;Zhou P;Lee SY
通讯作者：
Lee SY
影响因子：
64.8
作者：
Chung BC;Mashalidis EH;Tanino T;Kim M;Matsuda A;Hong J;Ichikawa S;Lee SY
通讯作者：
Lee SY
影响因子：
2.9
作者：
HEYDANEK, MG;STRUVE, WG;NEUHAUS, FC
通讯作者：
NEUHAUS, FC
影响因子：
3.2
作者：
Lloyd, AJ;Brandish, PE;Bugg, TDH
通讯作者：
Bugg, TDH
影响因子：
3.5
作者：
Bugg, Timothy D. H.;Rodolis, Maria T.;Jamshidi, Shirin
通讯作者：
Jamshidi, Shirin