Enterobactin- and salmochelin-β-lactam conjugates induce cell morphologies consistent with inhibition of penicillin-binding proteins in uropathogenic Escherichia coli CFT073.
Enterobactin- and salmochelin-β-lactam conjugates induce cell morphologies consistent with inhibition of penicillin-binding proteins in uropathogenic Escherichia coli CFT073.
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肠乳蛋白和咸蛋白-β-内酰胺偶联诱导细胞形态，与尿素学大肠杆菌CFT073中抑制青霉素结合蛋白的抑制一致。
DOI：
10.1039/d0sc04337k
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发表时间：
2021-01-13
期刊：
影响因子：
8.4
通讯作者：
Nolan EM
中科院分区：
文献类型：
--
作者：
Sargun A;Johnstone TC;Zhi H;Raffatellu M;Nolan EM
当病原体已知时，针对特定细菌菌株、物种或物种组的窄谱抗生素的设计和合成是治疗细菌感染的有希望的策略。在这项工作中，我们报告了四种新的铁载体-β-内酰胺缀合物的合成和评价，其中广谱β-内酰胺抗生素头孢氨苄（Lex）和美罗培南（Mem）通过稳定的聚乙二醇（PEG 3）接头共价连接到肠杆菌素（Ent）或二葡萄糖基化Ent（DGE）上。与母体抗生素相比，这些铁载体-β-内酰胺缀合物显示出对大肠杆菌增强的最小抑制浓度。尿致病性E. coliCFT 073中的结果表明，DGE-β-内酰胺类化合物靶向于病原体相关的儿茶酚铁载体受体IroN。对含有氨苄青霉素（氨苄青霉素）、Lex和Mem的铁载体-β-内酰胺的比较分析表明，DGE-Mem缀合物是有利的，因为它靶向IroN并表现出低的最小抑制浓度、快速的时间-杀灭动力学和对丝氨酸β-内酰胺酶的增强的稳定性。利用相差显微镜和荧光成像技术对大肠杆菌进行了研究。用铁载体-β-内酰胺缀合物处理的大肠杆菌显示与青霉素结合蛋白PBP 3（Ent/DGE-Lex/Lex）和PBP 2（Ent/DGE-Mem）的抑制一致的细胞形态。总之，这项工作阐明了Ent-和DGE-β-内酰胺缀合物对E.支持天然铁载体支架为缩小抗生素在临床应用中的活性谱和靶向致病性提供了机会。基于肠杆菌素和二葡萄糖基化肠杆菌素的铁载体-β-内酰胺缀合物进入尿路致病性大肠杆菌的周质。coliCFT 073通过FepA和IroN转运蛋白，并靶向青霉素结合蛋白。
The design and synthesis of narrow-spectrum antibiotics that target a specific bacterial strain, species, or group of species is a promising strategy for treating bacterial infections when the causative agent is known. In this work, we report the synthesis and evaluation of four new siderophore-β-lactam conjugates where the broad-spectrum β-lactam antibiotics cephalexin (Lex) and meropenem (Mem) are covalently attached to either enterobactin (Ent) or diglucosylated Ent (DGE) via a stable polyethylene glycol (PEG3) linker. These siderophore-β-lactam conjugates showed enhanced minimum inhibitory concentrations against Escherichia coli compared to the parent antibiotics. Uptake studies with uropathogenic E. coli CFT073 demonstrated that the DGE-β-lactams target the pathogen-associated catecholate siderophore receptor IroN. A comparative analysis of siderophore-β-lactams harboring ampicillin (Amp), Lex and Mem indicated that the DGE-Mem conjugate is advantageous because it targets IroN and exhibits low minimum inhibitory concentrations, fast time-kill kinetics, and enhanced stability to serine β-lactamases. Phase-contrast and fluorescence imaging of E. coli treated with the siderophore-β-lactam conjugates revealed cellular morphologies consistent with the inhibition of penicillin-binding proteins PBP3 (Ent/DGE-Amp/Lex) and PBP2 (Ent/DGE-Mem). Overall, this work illuminates the uptake and cell-killing activity of Ent- and DGE-β-lactam conjugates against E. coli and supports that native siderophore scaffolds provide the opportunity for narrowing the activity spectrum of antibiotics in clinical use and targeting pathogenicity. Siderophore-β-lactam conjugates based on enterobactin and diglucosylated enterobactin enter the periplasm of uropathogenic E. coli CFT073 via the FepA and IroN transporters, and target penicillin-binding proteins.
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DOI：
10.1016/j.bbapap.2008.11.005
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Delcour AH
通讯作者：
Delcour AH
影响因子：
16.1
作者：
Gao W;Chen Y;Zhang Y;Zhang Q;Zhang L
通讯作者：
Zhang L
影响因子：
5.4
作者：
Barczak, Amy K.;Hung, Deborah T.
通讯作者：
Hung, Deborah T.
影响因子：
6.4
作者：
Forsyth, Valerie S.;Himpsl, Stephanie D.;Mobley, Harry L. T.
通讯作者：
Mobley, Harry L. T.
影响因子：
3.3
作者：
Das, Chandan Kumar;Nair, Nisanth N.
通讯作者：
Nair, Nisanth N.