TARGETABLE BACTERICIDAL PROTEINS TO SPECIFICALLY KILL CLOSTRIDIUM DIFFICILE BACTE

特异性杀死艰难梭菌的靶向杀菌蛋白

• 批准号: 8549942
• 负责人: David William Martin
• 金额: $ 30万
• 依托单位: AVIDBIOTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549942
• 关键词: Antibiotic Resistance; Antibiotics; Antibodies; Bacteria; Bacteriocin Typing; Biological Assay; Clinical; Clostridium difficile; Collection; Colon; Diarrhea; Disease; Distal part of ileum; Dose; Drug Kinetics; Engineering; Gastrointestinal tract structure; Goals; Health; Hospitals; Human; Incidence; Infection; Inflammation; Intestines; Lead; Mus; North America; Nosocomial Infections; Oral; Oryctolagus cuniculus; Patients; Pharmacodynamics; Pharmacology; Phase; Process; Production; Proliferating; Proteins; Recombinant Proteins; Ribotypes; Ribotyping; Rifles; Role; Shotguns; Small Business Innovation Research Grant; Source; Specificity; System; Toxicology; Toxin; bactericide; high risk; improved; in vivo; innovation; killings; methicillin resistant Staphylococcus aureus; microbiome; mouse model; pathogen; pre-clinical; prevent

DESCRIPTION (provided by applicant): The ultimate goal of this proposal and any subsequent phase II proposal is to develop a unique protein agent to prevent Clostridium difficile associated diseases in those patients at high risk rather than wait to treat their dangerous and costly infections. We aim in this SBIR phase I project to determine the feasibility of oral delivery of a lead, specifically targeted bactericidal protein to eliminate C. difficile cariage without untended collateral damage to the intestinal microbiota. The lead candidate, termed a "diffocin", kills 27 of a collection of 28 BI/NAP1/027 strains; and Lawley et al (2010) have described a mouse model of C. difficile carriage. We have recently shown that another engineered R-type bacteriocin administered orally to rabbits can transit the GI tract to act as a specific bactericidal agent killing another bacterial pathogen in the terminal ileum and colon. Thus, after improving the lab scale production of this lead recombinant protein in B. subtilis and conducting preliminary pharmacology and pharmacodynamic studies to guide dosing, we shall evaluate the efficacy of diffocins in C57Bl/6 mice that are asymptomatic carriers and shedders of a sensitive strain of C. difficile. If diffocins eliminate C. difficile from carrier mice, the efect of oral diffocins on the mouse intestinal microbiota will be determined by ribotyping the fecal microbiome of normal and C. difficile carrier mice after diffocin administration.

描述（由申请人提供）：该提案和任何后续 II 期提案的最终目标是开发一种独特的蛋白质制剂来预防高危患者的艰难梭菌相关疾病，而不是等待治疗危险且昂贵的感染。我们在这个 SBIR 第一阶段项目中的目标是确定口服主要的、专门针对的杀菌蛋白的可行性，以消除艰难梭菌龋齿，而不会对肠道微生物群造成意外的附带损害。主要候选药物被称为“艰难梭菌素”，可杀死 28 种 BI/NAP1/027 菌株中的 27 种； Lawley 等人 (2010) 描述了艰难梭菌携带的小鼠模型。我们最近发现，另一种经改造的 R 型细菌素口服给兔子后，可以通过胃肠道，作为一种特定的杀菌剂，杀死回肠末端和结肠中的另一种细菌病原体。因此，在改进枯草芽孢杆菌中这种先导重组蛋白的实验室规模生产并进行初步药理学和药效学研究以指导剂量后，我们将评估艰难梭菌素在作为敏感菌株的无症状携带者和脱落者的 C57Bl/6 小鼠中的功效艰难梭菌。如果艰难梭菌素消除了携带者小鼠中的艰难梭菌，则口服艰难梭菌素对小鼠肠道微生物群的影响将通过在给予艰难梭菌素后对正常和艰难梭菌携带者小鼠的粪便微生物组进行核糖分型来确定。

项目成果

Phage tail-like particles kill Clostridium difficile and represent an alternative to conventional antibiotics.

噬菌体尾状颗粒可杀死艰难梭菌，是传统抗生素的替代品。

• DOI: 10.1016/j.surg.2014.06.015
• 发表时间: 2015
• 期刊: Surgery
• 影响因子: 3.8
• 作者: Sangster,William;Hegarty,JohnP;StewartSr,DavidB
• 通讯作者: StewartSr,DavidB

A modified R-type bacteriocin specifically targeting Clostridium difficile prevents colonization of mice without affecting gut microbiota diversity.

• DOI: 10.1128/mbio.02368-14
• 发表时间: 2015-03-24
• 期刊: mBio
• 影响因子: 6.4
• 作者: Gebhart D;Lok S;Clare S;Tomas M;Stares M;Scholl D;Donskey CJ;Lawley TD;Govoni GR
• 通讯作者: Govoni GR