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

蛋白质合成装置，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），四环素类和氯霉素类，靶向核糖体的小或大亚基。抗生素耐药菌的不断出现限制了许多抗生素的医学使用，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，而且还将为设计更好的抗微生物剂打开大门。此外，在存在和不存在药物的情况下，将确定耐抗生素细菌核糖体的结构，从而深入了解核糖体组分内的改变如何赋予高水平的抗生素耐药性，即使在药物仍然结合的情况下。除了抗生素，毒素，如RelE，靶向核糖体。这些毒素与其核糖体底物复合的结构将揭示其作用机制。最后，来自不同生物体的核糖体之间的微小差异导致药物结合的微小差异，这表明嗜酸性核糖体结构应该利用来自致病或密切相关物种的核糖体。因此，为了确定临床相关的核糖体-抗生素复合物，将改进来自芽孢杆菌属物种的核糖体大亚基的结晶。

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.