Gold Complexes with N-heterocyclic Carbene Ligands as Antibacterial Agents

越来越多的耐多药是细菌感染治疗中的一个主要问题。因此，开发具有新的化学结构和非常规作用方式的创新药物尤为重要。在一个中试项目中，发现了n -杂环碳烯配体有机金属金配合物（金- nhc配合物）对几种病原菌的高效抑制作用。特别是对耐甲氧西林金黄色葡萄球菌的高活性引起了人们的高度关注。此外，金- nhc配合物抑制细菌硫氧还蛋白还原酶（TrxR）的活性，与现有类型的抗生素相比，这是一种罕见的机制。本项目旨在合成金- nhc配合物，并对其作为抗菌TrxR抑制剂的潜力进行深入研究。此外，这些复合物将被纳入已知的抗生素中，并与可被主动运输到细胞中的靶向部分（金- nhc偶联物）相连。新化合物将进行详细的生物学评估，包括抗菌筛选、与TrxR相互作用的表征以及确定药物作用的替代模式。这些具有挑战性的目标将由来自Technische Universität Braunschweig（无机药物化学）和Helmholtz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来实现。

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).