Siderophore-Mediated Cargo Delivery to the Cytoplasm ofEscherichia coliandPseudomonas aeruginosa: Syntheses of Monofunctionalized Enterobactin Scaffolds and Evaluation of Enterobactin–Cargo Conjugate Uptake,Journal of the American Chemical Society

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Siderophore-Mediated Cargo Delivery to the Cytoplasm ofEscherichia coliandPseudomonas aeruginosa: Syntheses of Monofunctionalized Enterobactin Scaffolds and Evaluation of Enterobactin–Cargo Conjugate Uptake
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2012-10-25 , DOI: 10.1021/ja3077268
Tengfei Zheng ₁ , Justin L. Bullock ₁ , Elizabeth M. Nolan ₁

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The design and syntheses of monofunctionalized enterobactin (Ent, L- and D-isomers) scaffolds where one catecholate moiety of enterobactin houses an alkene, aldehyde, or carboxylic acid at the C5 position are described. These molecules are key precursors to a family of 10 enterobactin-cargo conjugates presented in this work, which were designed to probe the extent to which the Gram-negative ferric enterobactin uptake and processing machinery recognizes, transports, and utilizes derivatized enterobactin scaffolds. A series of growth recovery assays employing enterobactin-deficient E. coli ATCC 33475 (ent-) revealed that six conjugates based on L-Ent having relatively small cargos promoted E. coli growth under iron-limiting conditions whereas negligible-to-no growth recovery was observed for four conjugates with relatively large cargos. No growth recovery was observed for the enterobactin receptor-deficient strain of E. coli H1187 (fepA-) or the enterobactin esterase-deficient derivative of E. coli K-12 JW0576 (fes-), or when the D-isomer of enterobactin was employed. These results demonstrate that the E. coli ferric enterobactin transport machinery identifies and delivers select cargo-modified scaffolds to the E. coli cytoplasm. Pseudomonas aeruginosa PAO1 K648 (pvd-, pch-) exhibited greater promiscuity than that of E. coli for the uptake and utilization of the enterobactin-cargo conjugates, and growth promotion was observed for eight conjugates under iron-limiting conditions. Enterobactin may be utilized for delivering molecular cargos via its transport machinery to the cytoplasm of E. coli and P. aeruginosa thereby providing a means to overcome the Gram-negative outer membrane permeability barrier.

中文翻译：

铁载体介导的大肠埃希菌和铜绿假单胞菌细胞质的货物输送：单功能化肠杆菌素支架的合成和肠杆菌素-货物结合物摄取的评价

描述了单功能化肠杆菌素（Ent、L-和 D-异构体）支架的设计和合成，其中肠杆菌素的一个儿茶酚酸酯部分在 C5 位置包含烯烃、醛或羧酸。这些分子是这项工作中提出的 10 种肠杆菌素-货物偶联物家族的关键前体，旨在探索革兰氏阴性铁肠杆菌素摄取和加工机械识别、运输和利用衍生化肠杆菌素支架的程度。使用肠杆菌素缺陷型大肠杆菌 ATCC 33475 (ent-) 进行的一系列生长恢复分析表明，基于 L-Ent 的六种结合物具有相对较小的货物在铁限制条件下促进了大肠杆菌的生长，而生长恢复可忽略不计观察到具有相对较大货物的四种缀合物。对于肠杆菌素受体缺陷型大肠杆菌 H1187 菌株 (fepA-) 或肠杆菌素酯酶缺陷型大肠杆菌 K-12 JW0576 衍生物 (fes-)，或当肠杆菌素的 D-异构体为受雇。这些结果表明，大肠杆菌铁铁肠杆菌素运输机械可识别并递送选定的经货物修饰的支架至大肠杆菌细胞质。铜绿假单胞菌 PAO1 K648 (pvd-, pch-) 在肠杆菌素-货物结合物的摄取和利用方面表现出比大肠杆菌更大的混杂性，并且在铁限制条件下观察到八种结合物的生长促进。肠杆菌素可用于通过其运输机制将分子货物输送到大肠杆菌和 P. 的细胞质。

更新日期：2012-10-25

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