Phage resistance in Mycobacterium tuberculosis

结核分枝杆菌的噬菌体抗性

• 批准号: 10312805
• 负责人: Graham F. Hatfull
• 金额: $ 18.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312805
• 关键词: Address; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Bacteriophages; Biological Assay; Biology; Case Study; Clinical; Clinical Trials; Collection; DNA; Data; Engineering; Evaluation; Event; Extreme drug resistant tuberculosis; Face; Frequencies; Future; Genes; Genetic; Genomics; Goals; Growth; Human; Infection; Injections; Life; Longevity; Maps; Modeling; Monitor; Multidrug-Resistant Tuberculosis; Mutation; Mycobacteriophages; Mycobacterium abscessus; Mycobacterium smegmatis; Mycobacterium tuberculosis; Pathogenicity; Patients; Pattern; Persons; Pharmaceutical Preparations; Positioning Attribute; Predisposition; Rapid screening; Recombinants; Reporter; Reporting; Research Design; Resistance; Resistance development; Resistance profile; Therapeutic; Therapeutic Uses; Therapy trial; TimeLine; Tuberculosis; Uncertainty; Variant; Virulence; Virulent; Weight; absorption; base; clinical diagnosis; cystic fibrosis patients; design; drug-sensitive; expectation; experience; global health; mutant; pathogenic bacteria; personalized intervention; rapid diagnosis; rapid technique; rational design; research clinical testing; resistance mechanism; resistance mutation; resistant strain; success; targeted treatment; tool; transmission process; tuberculosis treatment

Tuberculosis remains a global health threat killing over 1.6 million people annually. Antibiotic treatment for drug-sensitive infections requires three antibiotics for a minimum of six months, and resistance to these antibiotics is common. Newly developed drugs are helpful for treating these resistant infections, but their longevity is challenged by the expectation of further resistances emerging. Tuberculosis is a potential target for therapeutic treatment with bacteriophages, which could be used to treat MDR-TB, XDR-TB, and TDR-TB infections, to shorten standard antibiotic therapy, to reduce the emergence of new resistant strains, to protect and extend the utility of newly developed antibiotics, and potentially to interfere with Mycobacterium tuberculosis transmission. Although phage therapy of TB may face substantial challenges – especially regarding access to the bacterial targets – encouragement is provided by a successful case study in treating a young Cystic Fibrosis patient with a highly antibiotic Mycobacterium abscessus infection. Moreover, the limited genetic variability of M. tuberculosis relative to other bacterial pathogens and preliminary data defining a set of potentially useful mycobacteriophages for treatment, sets the stage for clinical trials to determine if this is an effective and safe strategy for TB control. However, an important puzzle-piece is missing. Currently we know little about the mechanisms of M. tuberculosis resistance to the phages, the orthogonality of shared resistance profiles, or the impact of resistance mutations on virulence or antibiotic susceptibility. Without this, compiling therapeutic phage cocktails relies on guessing which phages are compatible based on genomic diversity, which may correlate only poorly with resistance and co-resistance profiles. Moreover, understanding the genetic basis of resistance provides much needed information required to monitor resistance development during phage therapy trials. Finally, the finding that resistance may commonly inhibit post-DNA injection events suggests that many resistance mechanisms can be thwarted by use of recombinant phages carrying counter-defense genes.

结核病仍然是全球健康威胁，每年丧生超过160万人。抗生素 对药物敏感感染的治疗至少需要三种抗生素，至少需要六个月 对这些抗生素的抗性很常见。新开发的药物有助于治疗 这些抗药性感染，但它们的寿命受到进一步期望的挑战 出现了阻力。结核病是治疗治疗的潜在靶标 可用于治疗MDR-TB，XDR-TB和TDR-TB感染的噬菌体 缩短标准抗生素疗法，以减少新的抗性菌株的出现，以保护 并扩展新开发的抗生素的效用，并有可能干扰 结核分枝杆菌的传播。尽管结核病的噬菌体疗法可能面临大量 挑战，尤其是关于进入细菌目标的挑战 - 提供了鼓励 通过一项成功治疗高度抗生素的年轻囊性纤维化患者的案例研究 分枝杆菌腹肌感染。此外，结核分枝杆菌的遗传变异有限 相对于其他细菌病原体和定义一组潜在有用的初步数据 分枝杆菌治疗，为临床试验设定了阶段，以确定这是否是 有效且安全的结核病控制策略。但是，缺少一个重要的难题。 目前，我们对结核分枝杆菌抗噬菌体的机制知之甚少， 共享抗性概况的正交性，或抵抗突变对病毒或 抗生素易感性。没有这个，编译治疗性噬菌体鸡尾酒依赖于猜测 哪些噬菌体是基于基因组多样性兼容的，这可能仅与 阻力和共抗性曲线。此外，了解抵抗的遗传基础 提供了在噬菌体期间监测阻力发展所需的急需信息 治疗试验。最后，发现耐药性通常会抑制DNA注射后注射 事件表明，可以通过使用重组来挫败许多电阻机制 带有反防御基因的噬菌体。

项目成果

Toward a Phage Cocktail for Tuberculosis: Susceptibility and Tuberculocidal Action of Mycobacteriophages against Diverse Mycobacterium tuberculosis Strains.

• DOI: 10.1128/mbio.00973-21
• 发表时间: 2021-05-20
• 期刊: mBio
• 影响因子: 6.4
• 作者: Guerrero-Bustamante CA;Dedrick RM;Garlena RA;Russell DA;Hatfull GF
• 通讯作者: Hatfull GF