Investigating nanobodies to target multidrug resistant bacterial pathogens

研究针对多重耐药细菌病原体的纳米抗体

• 批准号: 10225294
• 负责人: Bryan William Davies
• 金额: $ 68.66万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225294
• 关键词: American; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Antibodies; Antibody Therapy; Back; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Cessation of life; Chemistry; Complementarity Determining Regions; Conserved Sequence; Development; Failure; Future; Immune; Infection; Invaded; Lead; Length; Medical; Methods; Modality; Molecular; Molecular Target; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Nature; Peptide Antibiotics; Peptides; Pharmacology; Population; Property; Research; Risk; Slide; Structure; Surface; Surface Antigens; Testing; Therapeutic; Therapeutic Uses; Therapeutic antibodies; Toxin; Vertebral column; Work; antimicrobial; antimicrobial drug; antimicrobial peptide; base; cell envelope; fight against; immune function; in vivo; insight; lead optimization; microbiome; multi-drug resistant pathogen; nanobodies; novel therapeutics; pathogen; pathogenic bacteria; prevent; quantum; screening; small molecule; tool; translational impact

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. ! !

项目摘要。 虽然抗生素耐药性细菌感染率持续上升，但我们开发的新抗菌药物 已经停滞了。传统小分子的失败导致补货是军火库需求的发展 防止我们回到抗生素前医疗时代的替代方法。抗菌肽是 对多重耐药病原体非常有效，但药理学特性较差，阻碍了其发挥作用 体内使用。抗体具有优异的药理学特性，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治疗用途，尤其是在免疫受损人群中 多重耐药感染的风险。该提案的目的是开发一种新的治疗范式 将抗菌肽抗生素的直接作用与抗体结构的优点结合在一个单一的 抗菌剂。为了开发这种新模式，我们正在利用可变重量的独特品质 骆驼重链抗体的链结构域，称为 VHH 或纳米抗体。由高支持 我们开发了用于先导抗菌纳米抗体鉴定的通量方法，这种新范例 利用直接抗菌肽活性的优势，同时提供模块化的多重检测方法 肽在药理学上有益的纳米抗体骨架结构中的作用。我们的方法能够 识别广谱和靶向抗菌药物，以选择性地消除入侵的病原体。 此外，我们的方法未来有潜力利用免疫功能增强病原体 清除。该提案为抗感染研究带来了巨大的飞跃。完成计划 通过引入基于免疫的抗病毒新方向，预计工作将产生积极的转化影响。 感染疗法和用于领先抗菌纳米抗体发现的新高通量工具，这两者都将 支持对抗抗生素耐药细菌。 ！ ！