Gold Complexes with N-heterocyclic Carbene Ligands as Antibacterial Agents

作为抗菌剂的 N-杂环卡宾配体金配合物

• 批准号: 382040922
• 负责人: Professor Dr. Mark Brönstrup
• 金额: --
• 依托单位: Institut für Medizinische und Pharmazeutische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/382040922?language=en
• 关键词: Gold; Complexes; heterocyclic; Carbene; Ligands

Increasing multidrug resistance is a major concern in the therapy of bacterial infections. Therefore, the development of innovative drugs with new chemical structures and unconventional modes of action is of particular importance. In a pilot project the high efficiency of organometallic gold complexes with N-heterocyclic carbene ligands (gold-NHC-complexes) against several pathogenic bacterial strains was discovered. Especially the high activities against methicillin-resistant S. aureus were of high interest. Moreover, gold-NHC-complexes inhibited the activity of bacterial thioredoxin reductase (TrxR), which is an uncommon mechanism if compared with established types of antibiotics. The project aims at the synthesis and deeper investigation of the potential of gold-NHC-complexes as antibacterial TrxR inhibitors. Moreover, the complexes will be incorporated into known antibiotics and connected with targeting moieties that can be activelytransported into the cells (gold-NHC-conjugates). The new compounds will be subjected to a detailed biological evaluation, which includes antibacterial screening, characterisation of the interaction with TrxR and the identification of alternative modes of drug action. These challenging goals shall be achieved by an interdisciplinary project team consisting of scientists from Technische Universität Braunschweig (Inorganic Medicinal Chemistry) and the Helmholtz Centre for Infection Research (Chemical Biology).

增加的多药耐药性是细菌感染治疗中的主要问题。因此，开发具有新化学结构和非常规作用模式的创新药物尤为重要。在一个试点项目中，发现了具有N-杂环卡宾配体的有机金属金络合物（金-NHC-络合物）对几种病原细菌菌株的高效率。特别是对耐甲氧西林沙门氏菌的高活性。金黄色葡萄球菌引起高度关注。此外，金-NHC-复合物抑制细菌硫氧还蛋白还原酶（TrxR）的活性，如果与已建立的抗生素类型相比，这是一种不常见的机制。该项目旨在合成和深入研究金-NHC-络合物作为抗菌TrxR抑制剂的潜力。此外，复合物将被掺入已知的抗生素中，并与可以被主动转运到细胞中的靶向部分连接（金-NHC-缀合物）。新化合物将进行详细的生物学评价，其中包括抗菌筛选，与TrxR相互作用的表征以及药物作用的替代模式的鉴定。这些具有挑战性的目标将由来自布伦瑞克工业大学布伦瑞克（无机药物化学）和亥姆霍兹感染研究中心（化学生物学）的科学家组成的跨学科项目团队实现。