Identification of Bacterial Post-translational Modifications that Regulate Antimicrobial Resistance

这个博士项目的目的是确定调节细菌抗菌素耐药性的蛋白质翻译后修饰。耐药细菌每年在全球范围内导致超过70万人死亡，并已成为全球医疗体系的严重威胁。如果我们对抗菌素耐药性问题置之不理，到2050年，每年的死亡人数可能会上升到1000万。因此，显然有必要了解抗菌素耐药性的调节机制，因为这将促进针对细菌感染的新疗法的开发。翻译后修饰可以赋予修饰的蛋白质新的性质，包括蛋白质活性、亚细胞定位、相互作用伙伴和稳定性的变化。蛋白质组学的最新进展表明，广泛的细菌蛋白质，包括那些与耐药性相关的蛋白质，受到不同的翻译后修饰。然而，这些已确定的翻译后修饰的功能意义在很大程度上仍不清楚。为了解决这个问题，我们将在不同的学科中应用技术，包括：分析科学(以确定耐药细菌中唯一存在的翻译后修饰)。合成生物学(使用遗传密码扩展将氨基酸与翻译后修饰结合在一起)。化学生物学(描述特定的翻译后修饰在生化分析和细菌细胞中的功能)。我们的研究可能会揭示针对细菌感染的新的治疗目标，为后续的药物发现研究奠定基石。

This PhD project aims to identify protein post-translational modifications that regulate antimicrobial resistance of bacteria. Drug-resistant bacteria kill over 700,000 people a year worldwide and have become serious threats to global healthcare systems. If we leave the problem of antimicrobial resistance unattended, the annual death toll could rise to 10 million by 2050. Thus, there is a clear need to understand the regulatory mechanisms of antimicrobial resistance as it will facilitate development of new therapeutics against bacterial infection. Post-translational modifications can confer novel properties to the modified proteins, including changes in protein activity, subcellular localisation, interaction partners, and stability. Recent advances in proteomics have revealed that a wide range of bacterial proteins, including those relevant to drug resistance, are subjected to different post-translational modifications. However, the functional significance of these identified post-translational modifications remains largely unknown. To address this problem, we will apply techniques in different disciplines, including: Analytical science (to identify post-translational modifications uniquely present in drug-resistant bacteria). Synthetic biology (using genetic code expansion to incorporate amino acids with post-translational modifications). Chemical biology (to characterise the functions of specific post-translational modification in biochemical assays and bacterial cells). Our studies will likely reveal new therapeutic targets against bacterial infections, setting the corner stone for subsequent drug discovery research.