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，每年造成160多万人死亡。抗生素 药物敏感性感染的治疗需要三种抗生素至少六个月， 对这些抗生素的耐药性很常见。新开发的药物有助于治疗 这些耐药感染，但他们的寿命受到挑战的期望，进一步 阻力出现。结核病是一个潜在的治疗目标， 噬菌体可用于治疗耐多药结核病、广泛耐药结核病和耐多药结核病感染， 缩短标准抗生素治疗，以减少新的耐药菌株的出现， 并扩展新开发的抗生素的效用，并可能干扰 结核分枝杆菌传播。虽然结核病的噬菌体治疗可能面临大量的 挑战-特别是关于细菌目标的获取-提供了鼓励 通过一个成功的案例研究，在治疗一个年轻的囊性纤维化患者与高抗生素 结核分枝杆菌感染。此外，M.结核 相对于其他细菌病原体和初步数据定义了一组潜在有用的 用于治疗的分枝杆菌噬菌体，为临床试验奠定了基础，以确定这是否是一种 有效和安全的结核病控制策略。然而，一个重要的拼图丢失了。 目前对M.结核病对结核杆菌的耐药性 共享耐药谱的正交性，或耐药突变对毒力的影响，或 抗生素敏感性如果没有这个，编译治疗性噬菌体鸡尾酒依赖于猜测 基于基因组多样性，这两种植物是相容的，这可能与 电阻和共电阻曲线。此外，了解耐药性的遗传基础 提供了监测噬菌体期间抗性发展所需的急需信息 治疗试验最后，耐药性通常会抑制DNA注射后的 事件表明，许多耐药机制可以通过使用重组 携带着反防御基因。

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