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: 10670196
• 负责人: DEBORAH T HUNG
• 金额: $ 125.74万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670196
• 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; Joints; Label; Lead; Lectin; Libraries; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Methods; Modality; Multi-Drug Resistance; Penetration; 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; intravenous administration; mouse model; multi-drug resistant pathogen; 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 由于迅速发展的耐药性，诊所中的吸毒革兰氏阴性细菌是紧迫 菌株，常规抗生素无法穿透外细胞壁，而在体内药物毒性中脱靶。 抗菌肽（AMP）和其他小分子抗菌铅在临床前显示了有希望的 杀死多药耐药的革兰氏阴性病原体的测试，但在临床方面面临重大挑战 由于体内的治疗结果下降而导致的翻译。该提议解决了小说的短缺 通过利用病原体的细胞表面来实现多药抗革兰氏阴性病原体的治疗策略 聚糖和当地环境可提供抗菌作用载荷。长期循环的Pro-Proug结构将是 设计为系统地给药后选择性地针对感染部位的设计，并响应于 特有感染组织微环境的蛋白水解活性。所提出的抗菌剂，称为 抗菌偶联物（AMC）由病原体特异性靶向剂组成，一​​种微环境特异性 可切合的链接器和杀菌有效载荷。这种模块化设计允许探索不同的组件 优化共轭活动。拟议的AMC将在体外进行设计和广泛评估，并且 在动物模型中，由DRS组成的MIT联合团队的毒性和抗菌活性。 Sangeeta Bhatia， Timothy Lu，Laura Kiessling和Bradley Pentelute。他们的实验室将利用蛋白酶响应的专业知识 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 生物缀合和快速肽合成技术，以推动AMC的发展。 这种新的治疗方式具有多种优势：病原体靶标的高水平特异性将 限制宿主的毒性，可以使用较少选择性的抗微生物剂，结合物将增加 药代动力学和狭窄的光谱活性将避免一般阻力机制的传播 物种之间并限制对宿主微生物群的损害。项目的完成将产生潜在客户 抗菌结合物用于治疗耐药性革兰氏阴性感染。集体优化 铅化合物的治疗概况将确定可以在临床前试验中提出的顶级候选者， 有可能提供有效绕过获得的革兰氏阴性抗生素的治疗策略 反抗。