Building re-usable phage and antibiotic treatments via exploitation of bacteria-phage co-evolutionary dynamics

通过利用细菌-噬菌体共同进化动力学构建可重复使用的噬菌体和抗生素治疗方法

• 批准号: 10316238
• 负责人: Samuel Paul Brown
• 金额: $ 19.73万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-09 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316238
• 关键词: Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Attention; Bacteria; Bacterial Infections; Bacteriophages; Biological Assay; Caring; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cystic Fibrosis; Data; Development; Ensure; Evolution; Experimental Models; Face; Genetic; Genetic Diseases; Genotype; Health Services Accessibility; In Vitro; Investigational Therapies; Light; Medical; Mission; Modeling; Modification; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Nature; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Preparation; Pseudomonas aeruginosa; Public Health; Research; Research Personnel; Resistance; Resistance development; Retreatment; Sampling; Sputum; System; Testing; Therapeutic; Time; Treatment Efficacy; Work; arms race; bacterial resistance; chronic infection; cost; cystic fibrosis patients; design; evidence base; improved; novel; pathogen; receptor; stressor; therapy design; usability

Project Summary Chronic (long-term) bacterial infections are a major medical and public-health challenge, exacerbated by the rise in antibiotic resistance. As antibiotics often fail to treat these cases, increasing attention is turning to alternate therapeutics, including bacteriophage (phage) therapy. Like antibiotics, phage therapy faces the challenge of resistance. Unlike drugs, phages can evolve to overcome bacterial defenses, opening potential for co-evolutionary dynamics with their targets. Phage evolution has been flagged as a potentially useful attribute in enhancing total efficacy, but also as a pitfall in ensuring regulatory compliance due to the changing nature of required treatment. This application proposes that manipulating the co-evolutionary dynamic between bacteria and phage can promote the re-usability of defined phage treatments against a single evolving bacterial population. Co-evolution can occur in two main ways, an escalating ‘arms race dynamic’ (ARD) model, or a diversifying ‘fluctuating selection dynamic’ (FSD) model. Both are observed in phage-bacteria systems, and pilot data shows that FSD is favored by the addition of stressors including antibiotics. Pilot data further shows that FSD dynamics promote the effective re-use of a standard phage preparation against a single evolving bacterial population, as under the FSD regime, bacteria do not evolve broadly generalized resistance. Instead FSD leads to specialized resistance to the co-evolved phage at the cost of a return to susceptibility to the ancestral and potentially licensed/approved phage. The primary hypothesis is that co-evolutionary dynamics can be shifted with the addition of antibiotics – improving the long-term treatment efficacy by reducing bacterial burden and allowing for repeated application of a standard licensed phage preparation. The proposal will test this hypothesis in two specific aims: Aim 1: Assess co-evolutionary dynamics during clinical phage therapy using compassionate release patient samples. To assess co-evolutionary dynamics in a therapeutic context, the investigators will use clinical samples from 8 cystic fibrosis patients who received a phage cocktail as part of compassionate release care Aim 2: Identify phage and antibiotic factors that shift co-evolutionary dynamics in clinical PA isolates. Aim 1 provides a window into clinical co-evolutionary dynamics but does not allow a direct test of the impact of different treatment designs. To assess the factors that promote FSD co-evolutionary dynamics and treatment re-usability, the investigators will conduct in vitro mock phage therapy to recapitulate and expand on the compassionate release work in a synthetic sputum medium.

项目摘要 慢性（长期）细菌感染是一项重大的医疗和公共卫生挑战， 抗生素耐药性上升。由于抗生素往往不能治疗这些病例，越来越多的注意力转向 替代疗法，包括噬菌体（噬菌体）疗法。像抗生素一样，噬菌体疗法面临着 抵抗的挑战。与药物不同，抗生素可以进化以克服细菌的防御，从而为人类的免疫系统打开潜力。 共同进化的动力学。噬菌体进化已被标记为一个潜在的有用属性 在提高总体疗效方面，但由于 需要治疗。该应用提出，操纵细菌之间的共同进化动态 并且噬菌体可以促进针对单个进化细菌的确定的噬菌体处理的可重复使用性 人口 共同进化可以以两种主要方式发生，一种是不断升级的“军备竞赛动态”（ARD）模型，另一种是多样化的 “波动选择动态”（FSD）模型。两者都在噬菌体-细菌系统中观察到， 显示FSD受到包括抗生素在内的应激物的增加的青睐。试验数据进一步显示， 动力学促进了标准噬菌体制剂针对单一进化细菌的有效再利用 在FSD制度下，细菌不会进化出广泛的普遍耐药性。相反，FSD 导致对共同进化的噬菌体的特化抗性，代价是恢复对祖先噬菌体的易感性。 和潜在许可/批准的噬菌体。 主要的假设是，随着抗生素的加入，共同进化的动力学可以改变- 通过减少细菌负荷和允许重复施用来改善长期治疗功效 标准的噬菌体制剂。该提案将在两个具体目标中检验这一假设： 目的1：评估临床噬菌体治疗期间使用同情释放患者的协同进化动力学 样品为了评估治疗背景下的共同进化动力学，研究人员将使用临床 来自8名囊性纤维化患者的样本，这些患者接受噬菌体鸡尾酒作为同情释放护理的一部分 目的2：确定噬菌体和抗生素的因素，改变临床PA分离株的共同进化动力学。要求1 为临床共同进化动力学提供了一个窗口，但不允许直接测试 不同的治疗设计。评估促进FSD共同进化动力学和治疗的因素 可重复使用，研究人员将进行体外模拟噬菌体治疗，以概括和扩展 在合成痰液培养基中进行同情释放。

项目成果

Evolving antibiotic spectrum.

不断发展的抗生素光谱。

• DOI: 10.1073/pnas.2214267119
• 发表时间: 2022-10-11
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Waldetoft, Kristofer Wollein;Brown, Sam P.
• 通讯作者: Brown, Sam P.

The social lives of viruses and other mobile genetic elements: a commentary on Leeks et al. 2023.

病毒和其他移动遗传元素的社会生活：对 Leeks 等人的评论。

• DOI: 10.1111/jeb.14239
• 发表时间: 2023
• 期刊: Journal of evolutionary biology
• 影响因子: 2.1
• 作者: Irby,Iris;Brown,SamP
• 通讯作者: Brown,SamP

The dynamic response of quorum sensing to density is robust to signal supplementation and individual signal synthase knockouts.

• DOI: 10.1099/mic.0.001321
• 发表时间: 2023-05
• 期刊: MICROBIOLOGY-SGM
• 影响因子: 2.8
• 作者: Rattray, Jennifer B.;Kramer, Patrick J.;Gurney, James;Thomas, Stephen;Brown, Sam P.
• 通讯作者: Brown, Sam P.