Discovery and characterisation of novel ribosome-targeting antibiotics

核糖体和蛋白质合成代表细菌细胞内用于抑制的主要靶标之一。许多临床上重要类别的抗生素靶向核糖体，然而，病原菌的多重耐药性限制了它们的效用，强调迫切需要开发克服耐药性病原体的新型抗菌剂。开发管道和临床试验中的大多数化合物是目前使用的抗生素的半合成衍生物，并且基于天然产物祖化合物的化学支架。因此，希望发现和开发基于全新且不相关的化学支架并且在靶标上具有不同结合位点以避免与当前使用的抗生素交叉耐药性的新的抗微生物剂。该提案采用了一种经过验证的荧光报告系统来筛选新型抗菌剂，初步结果已经导致了两种新型支架的发现。将进行结构研究以确定这些化合物在核糖体上的结合位点，这将有助于设计、合成和筛选第二代衍生物。此外，我们已经开始对一系列特征不佳的核糖体靶向抗生素进行结构分析，这些抗生素具有不同的化学支架，因此可能靶向核糖体上的独特结合位点。结合一系列体外生物化学测定，我们的研究不仅将提供对这些化合物作用模式的机械见解，还将揭示蛋白质合成的基本过程。

The ribosome and protein synthesis represent one of the major targets within the bacterial cell for inhibition. Many clinically important classes of antibiotics target the ribosome, however, multi-drug resistance of pathogenic bacteria has limited their utility, emphasizing the desperate need to develop novel antimicrobials that overcome the antibiotic-resistance pathogens. The majority of compounds in the development pipeline and in clinical trials are semi-synthetic derivatives of currently used antibiotics and are based on the chemical scaffold of the natural product progenitor compound. Therefore, it is desirable to discover and develop new antimicrobial agents that are based on completely new and unrelated chemical scaffolds and that have distinct binding sites on the target to avoid cross-resistance with currently used antibiotics. This proposal employs a validated fluorescence reporter system to screen for novel antimicrobial agents, with preliminary results already leading to the discovery of two novel scaffolds. Structural studies will be conducted to ascertain the binding site of these compounds on the ribosome, which will aid design, synthesis and screening of second generation derivatives. In addition, we have initiated structural analysis of a range of poorly characterized ribosome-targeting antibiotics that have distinct chemical scaffolds and therefore may target unique binding sites on the ribosome. In conjunction with a range of in vitro biochemical assays, our studies will also provide not only mechanistic insight into the mode of action of these compounds, but also shed light onto the fundamental process of protein synthesis.