Insights into the mechanism of antibiotic and toxin inhibition of ribosome function and antibiotic-resistant ribosomal subunits, using X-ray crystallography.

利用 X 射线晶体学深入了解抗生素和毒素抑制核糖体功能和抗生素耐药核糖体亚基的机制。

• 批准号: 34302568
• 负责人: Professor Dr. Daniel Nicodemus Wilson
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/34302568?language=en
• 关键词: Insights; into; mechanism; antibiotic; toxin

The protein synthesizing apparatus, the ribosome, is one of the major targets for antibiotics within the cell. Many clinically important classes of antibiotics, such as macrolides (erythromycin), tetracyclines and chloramphenicols, target the small or large subunit of the ribosome. The ever-increasing emergence of antibiotic-resistant bacteria has restricted the medical usage of many antibiotics and led to the development of novel or improved inhibitors. Structures of such novel or improved drugs in complex with their target, the ribosome, will not only lead to an understanding into the mechanism of inhibition, but will also open the door to design of better antimicrobial agents. Additionally, structures of antibiotic-resistant bacterial ribosomes will be determined, in the presence and absence of the drug, providing insight into how alterations within the ribosomal components confer high-level antibiotic resistance, even in circumstances where the drug still binds. In addition to antibiotics, toxins, such as RelE, target the ribosome. Structures of these toxins in complex with their ribosomal substrate will shed light into their mechanism of action. Finally, small differences between ribosomes from different organisms leads to slight differences in drug binding, suggesting that antibioticribosome structures should utilize ribosomes from pathogenic, or closely related, species. Thus, crystallization of the large ribosomal subunit from Bacillus species will be improved in order to determine clinical relevant ribosome-antibiotic complexes.

蛋白质合成器，即核糖体，是细胞内抗生素的主要靶标之一。许多临床上重要的抗生素，如大环内酯类(红霉素)、四环素和氯霉素，针对核糖体的大小亚基。越来越多的抗生素耐药细菌的出现限制了许多抗生素的医用用途，并导致了新型或改进的抑制剂的开发。这种新型或改进的药物与其靶标核糖体复合的结构，不仅将导致对抑制机制的理解，而且将为设计更好的抗菌剂打开大门。此外，在药物存在和不存在的情况下，将确定耐药细菌核糖体的结构，从而深入了解核糖体成分的变化如何产生高水平的抗生素耐药性，即使在药物仍然结合的情况下也是如此。除了抗生素，REE等毒素还针对核糖体。这些毒素与核糖体底物的复合体结构将有助于揭示它们的作用机制。最后，来自不同生物的核糖体之间的微小差异导致药物结合的微小差异，这表明抗生素核糖体结构应该利用来自病原或密切相关物种的核糖体。因此，芽孢杆菌大核糖体亚基的结晶将被改进，以确定临床相关的核糖体-抗生素复合体。