Protein engineering for the development of novel antimicrobial agents

用于开发新型抗菌剂的蛋白质工程

• 批准号: 10351839
• 负责人: John S. Albin
• 金额: $ 19.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10351839
• 关键词: Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Biology; Cessation of life; Chemistry; Chemotaxis; Clinical; Combined Modality Therapy; Communicable Diseases; Complex; Defensins; Derivation procedure; Development; Engineering; Environment; Face; Funding; General Hospitals; Genomics; Goals; Gram-Negative Bacteria; Head; Home; Human; Human Engineering; Human body; Immune; Immune response; Immune system; Immunology; Infection; Institutes; K-Series Research Career Programs; Lead; Libraries; Life; Lipopolysaccharides; Malignant Neoplasms; Mammalian Cell; Maps; Mass Spectrum Analysis; Massachusetts; Mediating; Membrane; Mentors; Microbe; Microbiology; Natural Products; Pathogenesis; Peptide Synthesis; Phagocytes; Phenotype; Property; Protein Engineering; Proteome; Proteomics; Research; Research Training; Resistance; Resources; Scientist; Source; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Therapeutic Human Experimentation; Toxic effect; Training; United States; Work; antimicrobial; antimicrobial drug; antimicrobial peptide; antimicrobial peptide LL-37; attributable mortality; base; beta-Defensins; career; cathelicidin; cytotoxicity; drug development; experience; genetic approach; immunoregulation; insight; mortality; novel; novel antibiotic class; pathogen; pre-clinical; programs; rational design; recruit; small molecule

PROJECT SUMMARY Antimicrobial resistance increasingly threatens our ability to effectively treat a wide range of infections. Absent the development of novel antibiotics, humanity faces the prospect of a return to the pre-antibiotic era with associated mortality to rival that of cancer. One promising approach for the development of novel antibiotics is the engineering of antimicrobial peptides (AMPs), miniproteins of diverse structural classes made by all branches of life to defend against microbes. In particular, the engineering of human AMPs presents the opportunity to leverage both the antimicrobial and immunomodulatory properties of these AMPs to treat infections. Under the guidance of mentors at the Massachusetts Institute of Technology (MIT), Massachusetts General Hospital (MGH), and the Broad Institute, the candidate has adapted fast flow chemistry for the rapid synthesis and engineering of human AMPs, and in this proposal he seeks to extend these efforts through two aims. Aim 1 defines the structure-activity relationships underlying the mechanisms of gram-negative killing and phagocyte chemotaxis mediated by three human AMPs of distinct structural types, while Aim 2 extends these lines of inquiry to the development of derivatives of LL-37 as lead therapeutics. Together, these aims lay the groundwork for extension of the studies described to additional facets of AMP biology and engineering as well as preclinical applications as the candidate transitions to independence. The candidate’s research background consists of doctoral training in innate immunology against retroviral infection combined with clinical training in infectious diseases. This proposal for a K08 Mentored Clinical Scientist Research Career Development Award will enable the candidate to complete additional hands-on and didactic training in protein engineering and omics technologies over a five-year period toward the goal of establishing an independent, R01-funded research program applying these approaches to the ongoing study and development of human AMPs as novel antibiotics. In this effort, he is guided by primary mentors with expertise in protein engineering and mass spectrometry as well as bacterial pathogenesis and genomic technologies, which is further supported by an advisory board with deep expertise in microbiology, immunology, proteomics, AMP mechanisms of action, and drug development as well as the extensive resources of MIT, MGH, and the Broad Institute.

项目总结 抗菌素耐药性日益威胁着我们有效治疗各种感染的能力。缺席 随着新型抗生素的发展，人类面临着回到抗生素前时代的前景 相关死亡率与癌症不相上下。开发新型抗生素的一个有希望的方法是 抗菌肽(AMPs)的工程学，这是一种由所有人制造的不同结构类别的微型蛋白质 生命的分支来防御微生物。特别是，人类AMP的工程学提出了 利用这些AMP的抗菌和免疫调节特性来治疗 感染。在麻省理工学院导师的指导下，马萨诸塞州 综合医院(MGH)和博德研究所，应聘者已适应快速流动化学 人类AMP的合成和工程，在这个提案中，他试图通过两个 目标。目的1定义革兰氏阴性杀菌机制的结构-活性关系 三种不同结构类型的人AMP介导的吞噬细胞趋化作用，而Aim 2则扩展了这些 探索作为铅治疗药物的LL-37衍生物的开发。这些目标共同奠定了 为将所描述的研究扩展到AMP生物学和工程学的其他方面奠定基础 随着候选人向独立过渡，临床前的应用也是如此。 候选人的研究背景包括对抗逆转录病毒的天然免疫学博士培训 感染结合传染病临床培训。这份关于K08指导临床的建议 科学家研究职业发展奖将使候选人能够完成更多的实践和 为期五年的蛋白质工程和组学技术教学培训，以实现 建立独立的、由R01资助的研究计划，将这些方法应用到正在进行的研究中 以及人AMPS作为新型抗生素的开发。在这一努力中，他得到了主要导师的指导 在蛋白质工程和质谱学以及细菌致病和基因组学方面的专业知识 技术，进一步得到一个在微生物学方面拥有深厚专业知识的顾问委员会的支持， 免疫学、蛋白质组学、AMP作用机制、药物开发以及广泛的 麻省理工学院、麻省理工学院和博德研究所的资源。