(2S,5R,6R)-6-((R)-2-(hex-5-ynamido)-2-phenylacetamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | 1067890-47-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,5R,6R)-6-((R)-2-(hex-5-ynamido)-2-phenylacetamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
• 英文别名: (2S,5R,6R)-6-[[(2R)-2-(hex-5-ynoylamino)-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
• CAS: 1067890-47-4
• 化学式: C₂₂H₂₅N₃O₅S
• 分子量: 443.524
• InChiKey: HYGLYTRHAHLYOX-PDOICOKGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  141
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S,5R,6R)-6-((R)-2-(hex-5-ynamido)-2-phenylacetamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 在 三氟乙酸 作用下， 以 水 、 乙腈 为溶剂， 反应 24.0h， 以25%的产率得到(4S)-2-(((R)-2-(hex-5-ynamido)-2-phenylacetamido)methyl)-5,5-dimethylthiazolidine-4-carboxylic acid
  参考文献：
  名称：

  Enterobactin-Mediated Delivery of β-Lactam Antibiotics Enhances Antibacterial Activity against Pathogenic Escherichia coli

  摘要：

  The design, synthesis, and characterization of enterobactin antibiotic conjugates, hereafter Ent-Amp/Amx, where the beta-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent beta-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.

  DOI：

  10.1021/ja503911p
• 作为产物：
  描述：

  5-己炔酸 在 氯化亚砜 、 碳酸氢钠 作用下， 以 水 、 丙酮 为溶剂， 反应 2.0h， 生成 (2S,5R,6R)-6-((R)-2-(hex-5-ynamido)-2-phenylacetamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
  参考文献：
  名称：

  Enterobactin-Mediated Delivery of β-Lactam Antibiotics Enhances Antibacterial Activity against Pathogenic Escherichia coli

  摘要：

  The design, synthesis, and characterization of enterobactin antibiotic conjugates, hereafter Ent-Amp/Amx, where the beta-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent beta-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.

  DOI：

  10.1021/ja503911p

文献信息

• Enterobactin- and salmochelin-β-lactam conjugates induce cell morphologies consistent with inhibition of penicillin-binding proteins in uropathogenic <i>Escherichia coli</i> CFT073
  作者：Artur Sargun、Timothy C. Johnstone、Hui Zhi、Manuela Raffatellu、Elizabeth M. Nolan

  DOI：10.1039/d0sc04337k

  日期：——

  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

  当已知病原体时，设计和合成针对特定细菌菌株、物种或物种群的窄谱抗生素是治疗细菌感染的一种有前途的策略。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估，其中广谱β-内酰胺抗生素头孢氨苄（Lex）和美罗培南（Mem）共价连接到肠杆菌素（Ent）或二葡萄糖基化Ent（ DGE）通过稳定的聚乙二醇（PEG 3 ）连接体。与母体抗生素相比，这些铁载体-β-内酰胺缀合物对大肠杆菌的最低抑制浓度有所提高。对尿路致病性大肠杆菌CFT073 的摄取研究表明，DGE-β-内酰胺靶向病原体相关的儿茶酚酸铁载体受体 IroN。对含有氨苄青霉素 (Amp)、Lex 和 Mem 的铁载体-β-内酰胺的比较分析表明，DGE-Mem 缀合物具有优势，因为它以 IroN 为靶标，并表现出较低的最低抑制浓度、快速的杀伤动力学以及对丝氨酸 β 的增强的稳定性-内酰胺酶。用铁载体-β-内酰胺缀合物处理的大肠
• Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli
  作者：Phoom Chairatana、Tengfei Zheng、Elizabeth M. Nolan

  DOI：10.1039/c5sc00962f

  日期：——

  New antibiotics are required to treat bacterial infections and counteract the emergence of antibiotic resistance.

  需要新的抗生素来治疗细菌感染并对抗抗生素耐药性的出现。
• Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a β-Lactam to Gram-Negative Bacterial Pathogens
  作者：Rachel N. Motz、Chuchu Guo、Artur Sargun、Gregory T. Walker、Martina Sassone-Corsi、Manuela Raffatellu、Elizabeth M. Nolan

  DOI：10.1021/jacs.3c14490

  日期：2024.3.20

  new antibiotics and delivery strategies is of critical importance for treating infections caused by Gram-negative bacterial pathogens. Hijacking bacterial iron uptake machinery, such as that of the siderophore enterobactin (Ent), represents one promising approach toward these goals. Here, we report a novel Ent-inspired siderophore–antibiotic conjugate (SAC) employing an alternative siderophore moiety

  开发新的抗生素和给药策略对于治疗革兰氏阴性细菌病原体引起的感染至关重要。劫持细菌铁吸收机制，例如铁载体肠杆菌素（Ent），是实现这些目标的一种有前途的方法。在这里，我们报告了一种新型的 Ent 启发的铁载体-抗生素缀合物 (SAC)，采用替代铁载体部分作为递送载体，并证明了我们的 SAC 含有 β-内酰胺抗生素氨苄西林 (Amp) 对抗多种致病性革兰氏阴性细菌菌株的效力。我们建立了N,N',N'' -(次氮基三(乙烷-2,1-二基))三(2,3-二羟基苯甲酰胺) (TRENCAM，以下简称 TC)（Ent 的合成模拟物）促进药物的能力穿过革兰氏阴性病原体的外膜（OM）的传递。将 Amp 与新型单功能化 TC 支架结合得到 TC-Amp，与未修饰的 Amp 相比，TC-Amp 对胃肠道病原体鼠伤寒沙门氏菌 ( S Tm) 的抗菌活性显着增强。细菌摄取、抗生素敏感性和S Tm 显微镜研究表明，TC
• β-Lactams as Selective Chemical Probes for the in Vivo Labeling of Bacterial Enzymes Involved in Cell Wall Biosynthesis, Antibiotic Resistance, and Virulence
  作者：Isabell Staub、Stephan A. Sieber

  DOI：10.1021/ja803349j

  日期：2008.10.8

  With the development of anti biotic-resistant bacterial strains, infectious diseases have become again a life-threatening problem. One of the reasons for this dilemma is the limited number and breadth of current therapeutic targets for which several resistance strategies have evolved over time. To expand the number of addressable enzyme targets and to understand their function, activity, and regulation, we utilized a chemical proteomic strategy, called activity-based protein profiling (ABPP) pioneered by Cravatt, for the identification of beta-lactam-binding enzymes under in vivo conditions. In this two-tiered strategy, we first prepared a selection of conventional antibiotics for labeling diverse penicillin binding proteins (PBPs) and second introduced a new synthetic generation of beta-lactam probes, which labeled and inhibited a selection of additional PBP unrelated bacterial targets. Among these, the virulence-associated enzyme CIpP and a resistance-associated beta-lactamase were labeled and inhibited by selected probes, indicating that the specificity of beta-lactams can be adjusted to versatile enzyme families with important cellular functions.
• [EN] ENTEROBACTIN CONJUGATES AND USES THEREOF<br/>[FR] CONJUGUÉS D'ENTÉROBACTINE ET LEURS UTILISATIONS
  申请人：MASSACHUSETTS INST TECHNOLOGY

  公开号：WO2015057958A2

  公开（公告）日：2015-04-23

  The present invention provides novel enterobactin-cargo conjugates, such as compounds of Formula (I), and salts thereof, where X is the cargo and may be an antibiotic, a fluorophore, or biotin. The present invention also provides complexes, compositions, kits, and methods that involve the compounds of Formula (I) and are useful in delivering a cargo to a bacterium, treating a bacterial infection, cystic fibrosis, and/or inflammatory bowel disease in a subject, preventing a bacterial infection, cystic fibrosis, and/or inflammatory bowel disease in a subject, inhibiting the growth of or killing a bacterium, or determining the concentration of a bacterium in a biological sample. In certain embodiments, the bacterium is a Gram-negative bacterium.(I)