Esterase-Catalyzed Siderophore Hydrolysis Activates an Enterobactin–Ciprofloxacin Conjugate and Confers Targeted Antibacterial Activity,Journal of the American Chemical Society

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Esterase-Catalyzed Siderophore Hydrolysis Activates an Enterobactin–Ciprofloxacin Conjugate and Confers Targeted Antibacterial Activity
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-03-26 , DOI: 10.1021/jacs.8b01042
Wilma Neumann ₁ , Martina Sassone-Corsi ₂ , Manuela Raffatellu ₂ , Elizabeth M. Nolan ₁

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Enteric Gram-negative bacteria, including Escherichia coli, biosynthesize and deploy the triscatecholate siderophore enterobactin (Ent) in the vertebrate host to acquire iron, an essential nutrient. We report that Ent-Cipro, a synthetic siderophore-antibiotic conjugate based on the native Ent platform that harbors an alkyl linker at one of the catechols with a ciprofloxacin cargo attached, affords targeted antibacterial activity against E. coli strains that express the pathogen-associated iroA gene cluster. Attachment of the siderophore to ciprofloxacin, a DNA gyrase inhibitor and broad-spectrum antibiotic that is used to treat infections caused by E. coli, generates an inactive prodrug and guides the antibiotic into the cytoplasm of bacteria that express the Ent uptake machinery (FepABCDG). Intracellular hydrolysis of the siderophore restores the activity of the antibiotic. Remarkably, Fes, the cytoplasmic Ent hydrolase expressed by all E. coli, does not contribute to Ent-Cipro activation. Instead, this processing step requires IroD, a cytoplasmic hydrolase that is expressed only by E. coli that harbor the iroA gene cluster and are predominantly pathogenic. In the uropathogenic E. coli UTI89 and CFT073, Ent-Cipro provides antibacterial activity comparable to unmodified ciprofloxacin. This work highlights the potential of leveraging and targeting pathogen-associated microbial enzymes in narrow-spectrum antibacterial approaches. Moreover, because E. coli include harmless gut commensals as well as resident microbes that can contribute to disease, Ent-Cipro may provide a valuable chemical tool for strain-selective modulation of the microbiota.

中文翻译：

酯酶催化的铁载体水解激活肠杆菌素-环丙沙星缀合物并赋予靶向抗菌活性

肠道革兰氏阴性细菌，包括大肠杆菌，在脊椎动物宿主中生物合成和部署三儿茶酚酸铁载体肠杆菌素 (Ent) 以获得铁，一种必需的营养素。我们报告说 Ent-Cipro 是一种基于天然 Ent 平台的合成铁载体-抗生素偶联物，在其中一个邻苯二酚中带有一个烷基连接体，并附有环丙沙星货物，可针对表达病原体相关的大肠杆菌菌株提供靶向抗菌活性。 iroA 基因簇。铁载体附着在环丙沙星上，环丙沙星是一种 DNA 促旋酶抑制剂和广谱抗生素，用于治疗大肠杆菌引起的感染，产生一种无活性的前药，并将抗生素引导到表达 Ent 摄取机制 (FepABCDG) 的细菌的细胞质中. 铁载体的细胞内水解恢复了抗生素的活性。值得注意的是，Fes，一种由所有大肠杆菌表达的细胞质 Ent 水解酶，对 Ent-Cipro 的激活没有贡献。相反，该处理步骤需要 IroD，这是一种细胞质水解酶，仅由大肠杆菌表达，大肠杆菌具有 iroA 基因簇并且主要是致病性的。在尿路致病性大肠杆菌 UTI89 和 CFT073 中，Ent-Cipro 提供的抗菌活性与未修饰的环丙沙星相当。这项工作突出了在窄谱抗菌方法中利用和靶向病原体相关微生物酶的潜力。此外，因为大肠杆菌包括无害的肠道共生体以及可导致疾病的常驻微生物，

更新日期：2018-03-26

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