Innovative technologies to transform antibiotic discovery. Project 4 Infection site-specific amplification of antimicrobial conjugates

改变抗生素发现的创新技术。

• 批准号: 10463692
• 负责人: DEBORAH T HUNG
• 金额: $ 119.4万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463692
• 关键词: Address; Advanced Development; Aftercare; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antibodies; Bacteria; Bacteriophages; Biodistribution; Bypass; Cell Wall; Cell surface; Clinic; Clinical; Clinical Trials; Collaborations; Complement; Data; Death Rate; Development; Dose; Drug Kinetics; Drug toxicity; Engineering; Ensure; Environment; Enzymes; Gram-Negative Bacteria; Grant; Human; Image; In Vitro; Individual; Industrialization; Infection; Inferior; Intravenous; Joints; Label; Lead; Lectin; Libraries; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Methods; Modality; Multi-Drug Resistance; Peptide Hydrolases; Peptide Synthesis; Pharmaceutical Preparations; Polysaccharides; Preclinical Testing; Process; Prodrugs; Production; Proteins; Resistance; Serum; Site; Source; Specificity; Structure-Activity Relationship; Surface; Technology; Therapeutic; Thigh structure; Tissues; Toxic effect; Treatment Efficacy; Variant; antimicrobial; antimicrobial drug; antimicrobial peptide; bactericide; clinical translation; design; drug candidate; economic cost; flexibility; host microbiota; immunoregulation; improved; in vitro activity; in vivo; in vivo evaluation; innovative technologies; mouse model; nanomaterials; novel; novel therapeutics; pathogen; pharmacokinetics and pharmacodynamics; pneumonia model; pre-clinical; preclinical trial; resistance mechanism; resistant strain; response; small molecule; soft tissue; sortase; synthetic biology; targeted agent; therapy outcome; therapy resistant; treatment strategy

ABSTRACT Drugging Gram-negative bacteria in the clinic is an urgent unmet need due to rapidly-evolving resistant strains, the inability of conventional antibiotics to penetrate the outer cell wall, and off-target in vivo drug toxicities. Antimicrobial peptides (AMPs) and other small molecule antibacterial leads have shown promise in preclinical testing for killing multi-drug resistant Gram-negative pathogens, but have faced significant challenges in clinical translation as a result of inferior therapeutic outcomes in vivo. This proposal addresses the shortage of novel treatment strategies for multi-drug resistant Gram-negative pathogens by exploiting the pathogen's cell surface glycans and local environment to deliver antimicrobial payloads. Long-circulating, pro-drug constructs will be engineered that selectively target the site of infection after systemic administration and activate in response to proteolytic activity specific to the infected tissue microenvironment. The proposed antimicrobial agents, termed antimicrobial conjugates (AMCs) consist of a pathogen-specific targeting agent, a microenvironment-specific cleavable linker, and a bactericidal payload. This modular design allows the exploration of different components to optimize the conjugate's activity. The proposed AMCs will be designed and extensively evaluated in vitro and in animal models for toxicity and antimicrobial activity by a joint team at MIT composed of Drs. Sangeeta Bhatia, Timothy Lu, Laura Kiessling, and Bradley Pentelute. Their labs will leverage expertise with protease-responsive nanomaterials, synthetic biology and computational design, protein-glycan recognition processes, and bioconjugation and rapid peptide synthesis technologies, respectively, to advance the development of AMCs. This new therapeutic modality has several advantages: the high level of specificity for pathogen targets will limit toxicity to host, enabling the use of less selective antimicrobial agents, the conjugates will have increased pharmacokinetics, and the narrow spectrum activity will avoid the spread of general resistance mechanisms between species and limit damage to the host microbiota. Completion of the project will generate lead antimicrobial conjugates for the treatment of resistant Gram-negative infections. Collectively optimizing the therapeutic profiles of lead compounds will identify top candidates that can be advanced for pre-clinical trials, with the potential to deliver a therapeutic strategy that effectively bypasses acquired Gram-negative antibiotic resistance.

抽象的 由于耐药性迅速发展，在临床上对革兰氏阴性菌进行药物治疗是一个迫切的未满足的需求 菌株、传统抗生素无法穿透外细胞壁以及脱靶体内药物毒性。 抗菌肽 (AMP) 和其他小分子抗菌先导化合物已在临床前显示出前景 杀死多重耐药革兰氏阴性病原体的测试，但在临床上面临重大挑战 体内治疗效果较差的结果。该提案解决了新颖性的短缺 利用病原体细胞表面治疗多重耐药革兰氏阴性病原体的策略 聚糖和局部环境来提供抗菌有效负载。长循环的前药结构将 设计成在全身给药后选择性地靶向感染部位并响应 受感染组织微环境特有的蛋白水解活性。所提议的抗菌剂，称为 抗菌缀合物 (AMC) 由病原体特异性靶向剂、微环境特异性药物组成 可切割的接头和杀菌有效负载。这种模块化设计允许探索不同的组件 以优化缀合物的活性。拟议的 AMC 将在体外进行设计和广泛评估 麻省理工学院由博士组成的联合团队在动物模型中研究毒性和抗菌活性。桑吉塔·巴蒂亚, 蒂莫西·卢、劳拉·基斯林和布拉德利·彭特鲁特。他们的实验室将利用蛋白酶响应方面的专业知识 纳米材料、合成生物学和计算设计、蛋白质-聚糖识别过程，以及 生物共轭和快速肽合成技术分别推动AMC的发展。 这种新的治疗方式有几个优点：对病原体靶标的高度特异性将 限制对宿主的毒性，从而能够使用选择性较低的抗菌剂，缀合物将增加 药代动力学，窄谱活性将避免一般耐药机制的传播 物种之间的相互作用并限制对宿主微生物群的损害。项目完成后将产生铅 用于治疗耐药革兰氏阴性菌感染的抗菌结合物。共同优化 先导化合物的治疗概况将确定可以推进临床前试验的最佳候选药物， 有潜力提供一种有效绕过获得性革兰氏阴性抗生素的治疗策略 反抗。