Dynamic interplay between chloramphenicol/linezolid and the translating ribosome

P4（Wilson）的项目涉及抗生素和翻译装置之间的动态相互作用。在第一阶段，Wilson小组集中于临床上重要的四环素类抗生素。主要成就包括改进的四环素衍生物的结构和生物化学表征，确定药物的化学方面，提高抑制活性以及克服TetM介导的四环素耐药性。此外，我们提出了四环素耐药蛋白TetM与核糖体复合的近原子分辨率结构（与P3合作），为TetM如何从核糖体中去除药物以赋予四环素耐药性提供了分子见解。在第二阶段，威尔逊小组提出要解决核糖体抑制和耐氯霉素和恶唑烷酮抗生素的机制。具体而言，这些药物与新生多肽链相互作用以介导核糖体停滞，从而诱导下游抗性基因表达的机制将被研究。此外，将继续进行第一阶段（P5和P6合作）启动的脯氨酸停滞机制的生化研究，以及P7和P8正在进行的核糖体分析研究。总的来说，这样的研究提供了不同的核糖体配体如何与核糖体相互作用，以调节翻译装置的活性的机制的见解。

The projects of P4 (Wilson) address the dynamic interplay between antibiotics and the translational apparatus. In the first period, the Wilson group focused on the clinically important class of tetracycline antibiotics. Key achievements include a structural and biochemical characterization of improved tetracycline derivatives, identifying chemical aspects of the drug that improve the inhibitory activity as well as overcoming TetM-mediated tetracycline resistance. In addition, we present a near-atomic resolution structure of the tetracycline-resistance protein TetM in complex with the ribosome (in collaboration with P3), providing molecular insight into how TetM dislodges the drug from the ribosome to confer tetracycline resistance. In the second period, the Wilson group proposes to address the mechanism of ribosome inhibition and resistance to chloramphenicol and oxazolidinone antibiotics. Specifically, the mechanism by which these drugs interplay with the nascent polypeptide chain to mediate ribosome stalling, and thereby induce expression of downstream resistance genes will be investigated. Additionally, biochemical studies addressing the mechanism of proline stalling initiated in the first period (in collaboration P5 and P6) will be continued, as well as ribosome profiling studies that are in progress with P7 and P8. Collectively, such studies provide mechanistic insight into how diverse ribosomal ligands interplay with the ribosome to modulate the activity of the translational apparatus.