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Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics
ChemMedChem ( IF 3.6 ) Pub Date : 2018-03-23 , DOI: 10.1002/cmdc.201700793 Stefan Koppermann 1 , Zheng Cui 2 , Patrick D Fischer 1 , Xiachang Wang 3, 4 , Jannine Ludwig 1 , Jon S Thorson 2, 4 , Steven G Van Lanen 2 , Christian Ducho 1
ChemMedChem ( IF 3.6 ) Pub Date : 2018-03-23 , DOI: 10.1002/cmdc.201700793 Stefan Koppermann 1 , Zheng Cui 2 , Patrick D Fischer 1 , Xiachang Wang 3, 4 , Jannine Ludwig 1 , Jon S Thorson 2, 4 , Steven G Van Lanen 2 , Christian Ducho 1
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Muraymycins are a subclass of antimicrobially active uridine‐derived natural products. Biological data on several muraymycin analogues have been reported, including some inhibitory in vitro activities toward 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‐picomolar 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.
中文翻译：
天然存在的穆雷霉素核苷抗生素的靶标相互作用的见解
穆雷霉素是具有抗菌活性的尿苷衍生天然产物的一个亚类。几种穆雷霉素类似物的生物学数据已被报道，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，尚缺乏基于此类体外数据的针对天然存在的穆雷霉素的构效关系（SAR）研究。在这项工作中，我们报告了使用基于荧光的体外 MraY 测定对四个穆雷霉素亚组 A-D 的代表进行的详细 SAR 研究。对于某些穆雷霉素，观察到对MraY 的抑制作用，其IC 50值在低皮摩尔范围内。将这些抑制效力与抗菌活性进行比较，并与先前报道的与毛雷霉素抑制剂复合物的MraY X射线晶体结构得出的建模数据相关。总体而言，这些结果将为开发具有优化特性的穆雷霉素类似物作为抗菌候选药物铺平道路。
更新日期：2018-03-23
中文翻译：
天然存在的穆雷霉素核苷抗生素的靶标相互作用的见解
穆雷霉素是具有抗菌活性的尿苷衍生天然产物的一个亚类。几种穆雷霉素类似物的生物学数据已被报道，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，尚缺乏基于此类体外数据的针对天然存在的穆雷霉素的构效关系（SAR）研究。在这项工作中，我们报告了使用基于荧光的体外 MraY 测定对四个穆雷霉素亚组 A-D 的代表进行的详细 SAR 研究。对于某些穆雷霉素，观察到对MraY 的抑制作用，其IC 50值在低皮摩尔范围内。将这些抑制效力与抗菌活性进行比较，并与先前报道的与毛雷霉素抑制剂复合物的MraY X射线晶体结构得出的建模数据相关。总体而言，这些结果将为开发具有优化特性的穆雷霉素类似物作为抗菌候选药物铺平道路。
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