Fundamental Biophysical Study of the Antimicrobial Properties of Nisin for the Development of Novel Antibiotics

抗生素耐药性是一种可以避免的全球和经济健康威胁，预计到2050年每年将导致1000万人死亡。乳链菌肽是一种多环抗菌肽，对多种耐药菌株具有抗菌活性，对人体无毒，耐药率低。虽然乳酸链球菌素显示出有前途的治疗潜力，但其作用机制仍然知之甚少。因此，有必要推进生物物理方法和开发更有效的化学工具来探测乳酸链球菌素的抗菌作用模式。目前，可以理解的是，乳链菌肽表现出双重作用模式，基于脂质II（参与细菌细胞调节的关键化学物质）的螯合或纳米孔形成以破坏重要细胞离子梯度。然而，后一种假设缺乏纳米孔的详细表征。研究问题涉及纳米孔的大小、表面电荷和稳定性、它们的形成动力学以及可能的离子特异性。这些问题将在博士项目中通过从未用于乳酸链球菌素的电生理技术（包括聚合物孔径测量和离子通量测量）进行解决。此外，热力学方法，如等温滴定将被应用于了解膜结合和多聚化机制。新获得的生物物理学的见解将指导现代肽治疗的结构活性为基础的有机合成。通过促进新一代抗生素的开发，我们的方法有可能使制药行业和全球医疗保健受益。

Antimicrobial resistance is an avoidable global and economic health threat, projected to be responsible for 10 million deaths per annum by 2050. Nisin is a polycyclic antimicrobial peptide which is active against multi-drug resistant strains of bacteria and non-toxic to humans, and has low resistance rates. Although Nisin demonstrates promising therapeutic potential, its mechanism of action remains poorly understood. Hence, there is a need to advance biophysical methodology and develop more effective chemical tools to probe Nisin's antimicrobial mode of action. Currently, it is understood that Nisin exhibits a dual mode of action, based on either sequestration of Lipid II, a key chemical involved in bacterial cell regulation, or nanopore formation to disrupt vital cell ion gradients. The latter hypothesis lacks, however, detailed characterization of nanopores. Research questions relate to the size, surface charges and stability of the nanopores, their kinetics of formation, and possible ion specificity. These questions will be addressed in the PhD project via electrophysiological techniques which have never been used for Nisin including pore sizing with polymers and ion flux measurements. In addition, thermodynamic methods such as isothermal titration will be applied to understand the membrane binding and multimerization mechanism. The newly gained biophysical insight will guide the structure-activity based organic synthesis of modern peptide therapeutics. By facilitating development of a new generation of antibiotics, our approach has the potential to benefit the pharmaceutical industry and global healthcare.