Investigating nanobodies to target multidrug resistant bacterial pathogens

项目摘要。 虽然抗生素耐药性细菌感染的比率持续上升，但我们对新抗菌剂的开发 停滞不前传统小分子的失效导致重新库存是军火库发展的需求 来防止我们倒退到抗生素医学出现之前的时代抗菌肽是 对多药耐药病原体非常有效，但药理学性质差，阻碍了它们的 体内使用。抗体具有优良的药理学性质，但通常缺乏直接的抗微生物作用， 这限制了它们在治疗感染中的治疗用途，特别是在免疫受损人群中， 多药耐药感染的风险。这项建议的目的是发展一种新的治疗模式 它将抗微生物肽抗生素的直接作用与抗体结构的益处结合在一起， 抗菌剂为了开发这种新的模式，我们利用可变重的独特品质， 骆驼科重链抗体的链结构域，称为VHH或纳米抗体。支持高- 我们已经开发了用于先导抗菌纳米抗体鉴定的通量方法，这种新的范例 利用了直接抗微生物肽活性的益处，同时提供了一种模块化的方式来多重 肽作用于对免疫有益的纳米抗体骨架结构。我们的方法有能力 确定广谱和靶向抗菌剂，以选择性地消除入侵病原体。 此外，我们的方法具有利用免疫功能增强病原体的未来潜力。 间隙这一提议为抗感染研究提供了一个巨大的飞跃。完成计划的 这项工作有望通过引入基于免疫的抗- 感染治疗和新的高通量工具的领导抗菌纳米抗体的发现，这两个将 支持对抗抗生素耐药性细菌。 ! !

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. ! !