Phage depolymerases as antibiotics

噬菌体解聚酶作为抗生素

• 批准号: 9021386
• 负责人: JAMES J BULL
• 金额: $ 19.3万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9021386
• 关键词: Acinetobacter; Antibiotics; Antigens; Back; Bacteria; Bacterial Capsules; Bacterial Infections; Bacteriophages; Biological; Calibration; Cell Wall; Clinical; Cloning; Cytolysis; Development; Directed Molecular Evolution; Discipline; Endotoxins; Enzymes; Escherichia coli; Food; Foundations; Genomics; Gills; Goals; Immune; Immune system; Infection; Klebsiella pneumonia bacterium; Measures; Methods; Mus; Natural Products; Nature; Organism; Pathogenesis; Pharmaceutical Preparations; Phase; Plasmids; Polysaccharides; Population; Principal Investigator; Proteins; Protocols documentation; Research; Source; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Thick; Variant; Virus; Work; antimicrobial; antimicrobial drug; bacterial resistance; base; capsule; chemical property; enzyme activity; extracellular; improved; in vivo; interest; killings; lysin; pathogen; pathogenic bacteria; programs; public health relevance; standard care; success

 DESCRIPTION (provided by applicant): This project develops a new class of antimicrobial drug against capsulated bacteria. Capsules are thick layers of extracellular polysaccharides that hinder access of most antimicrobial agents to the underlying organisms. The therapeutic agents are protein enzymes - depolymerases - that degrade the bacterial capsule and expose the bacterium to attack by the immune system. These new antimicrobial agents should have moderately broad host ranges and work on bacteria resistant to classical drugs. They have the further advantage that they do not kill bacteria per se, merely enabling the immune system to do the killing, and they thus do not release endotoxins that would exacerbate symptoms. The biological sources of these enzymes used in this work are bacteriophages, viruses that kill bacteria, which are easily isolated from the wild. Instead of using intact bacteriophages, we propose to use just the enzymes, which are encoded as parts of the bacteriophage tailspike. Sporadic studies dating back 84 years suggest that the enzymes alone can effect a cure for bacterial infections. The work here will establish the generality of earlier work, developing and implementing a protocol for the isolation, identification, and calibration of depolymerase activity against arbitrary capsule types. The ultimate test provided here will be testing depolymerase efficacy in actual infections. A second direction of the work is to develop a protocol for evolving higher and broader activity of depolymerases, improving on native enzymes obtained from the wild. The work here focuses on Klebsiella pneumoniae and E. coli, with extension to Acinetobacter baumanii in the later phases.

 描述（由申请人提供）：该项目开发了一类新的抗胶囊化细菌的抗菌药物。胶囊是细胞外多糖的厚层，其阻碍大多数抗微生物剂进入下层生物体。治疗剂是蛋白酶-解聚酶-降解细菌荚膜并使细菌暴露于免疫系统的攻击。这些新的抗菌药物应该具有适度广泛的宿主范围，并对对经典药物耐药的细菌起作用。它们具有进一步的优点，即它们本身不杀死细菌，仅仅使免疫系统能够杀死细菌，因此它们不会释放会加剧症状的内毒素。这项工作中使用的这些酶的生物来源是噬菌体，即杀死细菌的病毒，它们很容易从野外分离出来。我们不使用完整的噬菌体，而是建议只使用酶，这些酶被编码为噬菌体尾刺的一部分。可追溯到84年前的零星研究表明，单独的酶可以治愈细菌感染。这里的工作将建立早期工作的一般性，开发和实施解聚酶活性的分离，鉴定和校准的协议 针对任意胶囊类型。这里提供的最终测试将测试解聚酶在实际感染中的功效。工作的第二个方向是制定一个协议， 更高和更广泛的解聚酶活性，改善从野生获得的天然酶。本研究的重点是肺炎克雷伯菌和大肠杆菌。大肠杆菌，并在后期扩展到鲍曼不动杆菌。