Protein engineering for the development of novel antimicrobial agents

项目摘要 抗生素耐药性日益威胁着我们有效治疗各种感染的能力。缺席 随着新型抗生素的开发，人类面临着回到前抗生素时代的前景， 与癌症的死亡率相当。开发新型抗生素的一种有前途的方法是 抗微生物肽（AMP）的工程化，各种结构类别的微蛋白， 抵御微生物的能力。特别是，人类抗菌肽的工程设计呈现出 利用这些AMP的抗微生物和免疫调节特性来治疗 感染.在马萨诸塞州的马萨诸塞州理工学院（MIT）导师的指导下， 总医院（MGH）和布罗德研究所，候选人已经适应了快速流动化学的快速 合成和人类AMP的工程，并在这一建议，他试图通过两个扩展这些努力 目标。目的1定义了革兰氏阴性杀伤机制的结构-活性关系， 吞噬细胞趋化性由三种不同结构类型的人AMP介导，而Aim 2扩展了这些 研究方向是开发LL-37衍生物作为先导治疗剂。总之，这些目标奠定了 为将所述研究扩展到AMP生物学和工程学的其他方面奠定了基础 作为临床前应用，因为候选人过渡到独立。 候选人的研究背景包括抗逆转录病毒的先天免疫学博士培训 感染与传染病临床培训相结合。K 08指导临床的提案 科学家研究职业发展奖将使候选人能够完成额外的实践， 在蛋白质工程和组学技术的教学培训，在五年内实现的目标， 建立一个独立的，R 01资助的研究计划，将这些方法应用于正在进行的研究 以及开发人AMP作为新型抗生素。在这一努力中，他受到主要导师的指导， 在蛋白质工程和质谱以及细菌致病和基因组方面的专业知识 技术，并得到一个在微生物学方面具有深厚专业知识的咨询委员会的进一步支持， 免疫学、蛋白质组学、AMP作用机制和药物开发以及广泛的 麻省理工学院，MGH和布罗德研究所的资源。

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.