Developing Membrane Targeting Antimicrobial Lipo-Peptoids by Modular Peptidomimicry and High Throughput Imaging

根据世界卫生组织的数据，抗菌素耐药性（AMR）是对公共卫生的最严重威胁之一，每年在欧洲造成33，000人死亡。以及生产力的损失和医疗成本的增加。开发新的抗菌剂是对抗AMR的重要工具，但发现对微生物具有高选择性（即对人类毒性低）的分子是困难的。此外，用于识别新型抗菌剂的典型生物测定和显微镜筛选工具在筛选效率和提供足够的信息以告知驱动创新的机制理解之间存在权衡。在这个项目中，我们的目标是利用一种新的高速，高分辨率的显微镜技术，从根本上提高筛选一类新的拟肽抗菌剂的质量和吞吐量。特别是，初步结果表明，我们的“膜靶向抗菌（脂）肽”（mTAP）应该能够灵活调节抗微生物活性和细胞毒性。成功鉴定一类新型靶向抗菌剂及其后续开发将对制药部门和公共卫生产生极大的兴趣。所提出的方法也有很大的潜力，以加速筛选其他疗法。方法学和治疗学方面都将是对抗AMR的实质性步骤。此外，新疗法和对抗AMR完全符合联合国可持续发展目标（SDG）3的良好健康和福祉。新的方法论也将加强欧洲的科学基础设施和经济。

According to the World Health Organization, antimicrobial resistance (AMR) is one of the gravest threats to public health, causing already 33,000 lives lost in Europe p.a. and more globally, as well as lost productivity and increased healthcare costs. Developing new antimicrobials is an important tool for combating AMR, but discovering molecules with high selectivity for microbes (i.e. low toxicity for humans) is difficult. Moreover, typical biological assay and microscopy screening tools for identifying novel antimicrobials have a trade-off between screening efficiency and providing sufficient information to inform mechanistic understanding for driving innovation. In this project we aim to take advantage of a novel high speed, high resolution microscopy technique to fundamentally improve the quality and throughput of screening a new class of peptide-mimetic antimicrobials. In particular, preliminary results show that our "membrane targeting antimicrobial (lipo)peptoids" (mTAPs) should enable flexible modulation of antimicrobial activity and cell toxicity. Successful identification of a novel class of targeting antimicrobials and its subsequent development will be of great interest to both the pharmaceutical sector and to public health. The proposed methodology also has great potential to accelerate screening of other therapeutics. Both the methodological and therapeutics aspects will be substantive steps to the fight against AMR. Moreover, novel therapeutics and combating AMR are fully consistent with the UN's Sustainability Development Goal (SDG) 3 in Good Health and Wellbeing. The novel methodological approaches will also strengthening Europe's scientific infrastructure and the economy.