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）是对公共卫生最严重的威胁之一，在欧洲每年已经造成3.3万人死亡，在全球范围内造成的死亡人数更多，还造成生产力损失和医疗成本增加。开发新的抗菌剂是对抗抗菌素耐药性的重要工具，但发现对微生物具有高选择性（即对人类低毒性）的分子是困难的。此外，用于鉴定新型抗菌素的典型生物测定和显微镜筛选工具需要在筛选效率和提供足够的信息之间进行权衡，以便为推动创新提供机制理解。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肽类抗微生物药物的质量和通量。特别是，初步结果表明，我们的“膜靶向抗菌（脂）肽”（mtap）应该能够灵活地调节抗菌活性和细胞毒性。成功鉴定一类新的靶向抗微生物药物及其后续发展将对制药部门和公共卫生产生重大影响。提出的方法也有很大的潜力，以加快筛选其他治疗方法。方法和治疗方面都将是对抗抗菌素耐药性的实质性步骤。此外，新疗法和抗抗生素耐药性完全符合联合国关于良好健康和福祉的可持续发展目标3。新的方法方法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.