Investigating nanobodies to target multidrug resistant bacterial pathogens

项目摘要。 在抗药性细菌感染率持续上升的同时，我们开发新的抗菌剂 已经停滞不前。传统小分子的失败导致补货是军火库发展的需要 防止我们回到抗生素出现前的医学时代的替代方法。抗菌肽是 对多重耐药病原体非常有效，但药理特性较差，阻碍了他们的 活体使用。抗体具有很好的药理特性，但通常缺乏直接的抗菌作用， 这限制了它们在治疗感染方面的使用，特别是在免疫功能低下的人群中 多药耐药感染的风险。这项提议的目标是开发一种新的治疗模式。 这将抗菌肽抗生素的直接作用与抗体结构的好处结合在一起 抗菌剂。为了开发这种新的模式，我们正在利用Variable Heavy的独特品质 骆驼重链抗体的链段，称为VHH或纳米体。由一个高位支撑- 我们开发了用于铅抗菌纳米体鉴定的吞吐量方法，这一新范式 利用直接抗菌肽活性的优势，同时提供一种模块化的多路传输方式 多肽在药理上有益的纳米体主骨架结构中的作用。我们的方法有能力 识别广谱和靶向抗菌剂，以选择性地消除入侵的病原体。 此外，我们的方法未来有可能利用免疫功能来增强病原体。 通行证。这项提议在抗感染研究方面带来了巨大的飞跃。完成计划中的 这项工作有望通过引入基于免疫的抗-HBs的新方向而产生积极的翻译影响 感染疗法和新的高通量工具，用于发现领先的抗微生物纳米体，两者都将 支持抗击抗药性细菌。 好了！ 好了！

Project Summary. While rates of antibiotic resistance bacterial infections continue to rise, our development of new antimicrobials has stagnated. The failure of traditional small molecule leads to restock are arsenal demands the development of alternative approaches to prevent our slide back to the pre-antibiotic medical era. Antimicrobial peptides are highly effective against multidrug resistant pathogens but have poor pharmacological properties hindering their in vivo use. Antibodies have excellent pharmacological properties but generally lack direct antimicrobial action, which limits their therapeutic use in treating infection, especially in immune compromised populations most at risk for multidrug resistant infection. The objective of this proposal is to develop a new therapeutic paradigm that joins the direct action of antimicrobial peptide antibiotics with the benefits of antibody structure in a single antimicrobial agent. To develop this new modality we are leveraging the unique qualities of variable heavy chain domain of Camelid heavy chain antibodies, known as a VHH or nanobody. Supported by a high- throughput approaches for lead antimicrobial nanobody identification we have developed, this new paradigm takes advantage of the benefit of direct antimicrobial peptide activity while providing a modular way to multiplex peptide action in a pharmacologically beneficial nanobody backbone structure. Our approach has the ability to identify both broad spectrum and target antimicrobials to selectively eliminate invading pathogens. Furthermore, our approach has the future potential to utilize immune functions for enhanced pathogen clearance. This proposal offers a quantum leap forward in anti-infective research. Completion of the planned work is expected to have a positive translational impact by introducing a new direction in immune based anti- infective therapy and new high-throughput tools for lead antimicrobial nanobody discovery, both of which will support the fight against antibiotic resistant bacteria. ! !