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.

结核病仍然是一个全球健康威胁，每年导致160多万人死亡。抗生素 对药物敏感感染的治疗需要三种抗生素，至少持续六个月， 对这些抗生素的抗药性是很常见的。新开发的药物有助于治疗 这些具有抵抗力的感染，但它们的寿命受到进一步 抵抗力正在显现。结核病是一种潜在的治疗靶点 可用于治疗耐多药结核、广泛耐药结核和结核分枝杆菌感染的噬菌体，以 缩短标准抗生素治疗，减少新耐药菌株的出现，以保护 并扩大新开发的抗生素的用途，并有可能干扰 结核分枝杆菌传播。尽管结核的噬菌体疗法可能面临实质性的 挑战--特别是在接触细菌靶标方面--提供了鼓励 一例青年囊性纤维化患者应用高效抗生素治疗的成功案例 脓肿分枝杆菌感染。此外，结核分枝杆菌有限的遗传变异性 相对于其他细菌病原体和定义了一组潜在有用的 用于治疗的分支杆菌噬菌体，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战略。然而，一块重要的拼图遗失了。 目前，我们对结核分枝杆菌对噬菌体的抗性机制知之甚少。 共享抗药性图谱的正交性，或抗药性突变对毒力或 抗生素敏感性。如果没有这一点，编制治疗性噬菌体鸡尾酒依赖于猜测 基于基因组多样性，哪些噬菌体是相容的，这可能只与 阻力和共阻力曲线。此外，了解抗药性的遗传基础 提供监控噬菌体过程中耐药性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 事件表明，许多耐药机制可以通过使用重组 携带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