Interrogating the nisin:lipid II interaction: a chemical biology approach

探究乳链菌肽：脂质 II 相互作用：化学生物学方法

• 批准号: EP/V033808/1
• 负责人: Alethea Tabor
• 金额: $ 96.74万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV033808%2F1
• 关键词: Interrogating; nisin; lipid; II; interaction

Antibiotic resistant bacterial infections are becoming an increasing threat to global public health. A recently published UK Government document, the O'Neill report (2016) estimates that 10 million lives a year could be lost by 2050 if we do not tackle this issue. Part of the problem is that little investment in new antimicrobials has taken place in industry in decades, with the last new class of antibiotics discovered over 30 years ago. This has generated a renewed interest in natural products as a source of potent antimicrobial drugs. One class of natural products that are being intensively studied as possible leads are the lantibiotics. The best known of these, nisin, is produced by one strain of bacteria in order to kill off competing bacteria, and has been successfully used as a food preservative for many years. However, its complex structure, difficulties in synthesis, and poor biological properties mean that is has not yet been exploited as a possible antimicrobial drug to combat bacterial infections in humans. It is known that nisin targets a complex lipid, lipid II, which is only found in bacteria. As lipid II is critical for bacteria to be able to synthesise their cell wall, it is difficult for bacteria to evolve resistance to antimicrobial agents that target lipid II. Importantly, nisin and lipid II fit together to form an ordered pore structure that results in rupture of the bacterial membrane and the death of the bacterial cell. It is therefore very important that we understand how this pore forms and what the important interactions are between the nisin and lipid II components: however, current techniques for studying the structure of pores in membranes do not have high enough resolution to see the details of these interactions.The collaborating research groups have previously developed powerful methods for synthesising the challenging structures of nisin and lipid II, for analyzing how pore form in lipid membranes, and for screening new antibacterials against pathogens such as MRSA. In this proposal, we will systematically design and synthesise variants of nisin and lipid II, and for each structural variation we will then try to assemble the pore complex. The process will be akin to piecing together a 3-D jigsaw at the nanoscale, varying each of the pieces of the jigsaw one by one, to see which parts of the nisin and lipid II are crucial to successful assembly, and which parts are not involved in complex formation. This information will lead to a detailed model for the nisin:lipid II pore structure, and will eventually enable pharmaceutical companies to design simplified lantibiotics as leads for next generation antimicrobials.

抗生素耐药的细菌感染正在成为对全球公共卫生的越来越多的威胁。最近发布的英国政府文件《奥尼尔报告》（O'Neill Report）（2016年）估计，如果我们不解决这个问题，到2050年，一年一年可能会丧生1000万。问题的一部分是，几十年来，对新抗菌剂的投资很少发生，最后一类新的抗生素是30年前发现的。这引起了对天然产物的新兴趣，作为有效抗菌药物的来源。一类对可能销售铅进行深入研究的天然产品是盐源生物。其中最著名的是尼生素，是由一种细菌菌株生产的，以杀死竞争细菌，并成功用作食品防腐剂多年。但是，其复杂的结构，合成困难和生物学性质差意味着尚未被用作可能的抗菌药物来打击人类的细菌感染。众所周知，尼宁靶向复杂的脂质脂质II，仅在细菌中发现。由于脂质II对于能够合成其细胞壁至关重要，因此细菌很难发展靶向脂质II的抗菌剂的抗性。重要的是，尼沙肽和脂质II融合在一起，形成有序的孔结构，从而导致细菌膜破裂和细菌细胞的死亡。因此，非常重要的是要我们了解这种孔以及尼生和脂质II成分之间的重要相互作用是什么：但是，当前的技术用于研究膜中毛孔的结构没有足够高的分辨率来查看这些相互作用的细节。并筛选针对MRSA等病原体的新抗菌物。在此提案中，我们将系统地设计和综合尼霉素和脂质II的变体，对于每种结构变化，我们将尝试组装孔复合物。该过程类似于将纳米级的3-D拼图拼凑在一起，将拼图的每一部分变化，以查看Nisin和Lipid II的哪些部分对于成功的组装至关重要，并且哪些部分与哪些部分不涉及复杂形成。这些信息将导致尼生蛋白的详细模型：脂质II孔结构，并最终使制药公司能够将简化的甘拟酰亚生生物设计为下一代抗菌剂的铅。