Novel Strategies for Treating Biofilm-Forming Pathogens with Phage Therapy

用噬菌体疗法治疗生物膜形成病原体的新策略

基本信息

批准号：
10320958
负责人：
John Joseph Dennehy
金额：
$ 19.25万
依托单位：
QUEENS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320958
关键词：
Ambush Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Area Bacteria Bacterial Genome Bacterial Infections Bacteriophages Biology Bypass Cells Cellular Stress Centers for Disease Control and Prevention (U.S.)Characteristics Clinical Combating Antibiotic Resistant Bacteria Communities Containment Coupling Cytolysis DNA Development Environmental Hazards Exposure to Genome Goals Growth Guanosine Monophosphate Health Heterogeneity Infection Knowledge Label Lead Lytic Lytic Phase Medicine Microbial Biofilms Mitomycin C Multi-Drug Resistance Pathway interactions Patients Penicillins Periodicity Pharmaceutical Preparations Progress Reports Prophages Research Resistance Signal Transduction Signaling Molecule Site Smoke Stress Testing Virulence Factors Work antimicrobial antineoplastic antibiotics biological adaptation to stress chemotherapy clinically relevant design dimer drug resistant pathogen effective therapy extracellular healthcare-associated infections innovation migration novel novel strategies pathogen response success therapy development

项目摘要

Project Summary The growing antibiotic resistance problem requires that we urgently develop and test new approaches to controlling bacterial infections. Phage therapy approaches offer great promise, but significant knowledge gaps currently exist that limit their application. Two issues that currently limit the broader use of phage therapy are the problem of curating specific lytic phage strains for each infection, and the difficulty of delivering phages directly to the infection sites where they are needed. We hypothesize that bacterial pathways that typically promote biofilm-associated growth can be decoupled from the stress- response pathways capable of inducing resident prophages. By separating these cellular responses, we propose to stabilize biofilms while also inducing temperate phages already present in the bacterial genome to enter lytic phase and kill the host cell. In so doing, we effectively bypass the limitations imposed by finding and delivering strain matched lytic phages to infections, while also developing approaches that make use of temperate phage therapy approaches. In Aim 1, we propose to determine biofilm dispersal rates and ascertain how biofilm-associated growth can be manipulated using cellular pathways. In Aim 2, we will analyze mechanisms by which lysogens can be induced into lytic phase to kill their hosts without spreading virulence factors beyond the biofilm. In Aim 3, we reinforce the approaches of the previous aims with an optimized lytic phage ambush of any escaping dispersers. The goals of this proposal are to develop an innovative, multi-pronged approach to phage therapy for biofilm-associated bacteria while also increasing overall knowledge of the limits and applicability of phage therapy.

项目概要日益严重的抗生素耐药性问题要求我们紧急开发和测试新方法以控制细菌感染。噬菌体治疗方法前景广阔，但意义重大目前存在的知识差距限制了其应用。目前限制更广泛的两个问题使用噬菌体疗法的问题是针对每种感染制定特定的裂解噬菌体菌株，以及将噬菌体直接输送到需要它们的感染部位很困难。我们假设通常促进生物膜相关生长的细菌途径可以与压力脱钩。能够诱导驻留前噬菌体的反应途径。通过分离这些细胞反应，我们建议稳定生物膜，同时诱导细菌中已经存在的温和噬菌体基因组进入裂解阶段并杀死宿主细胞。这样做，我们有效地绕过了限制通过寻找和传递菌株匹配的裂解噬菌体来进行感染，同时也发展利用温和噬菌体治疗方法的方法。在目标 1 中，我们建议确定生物膜分散率并确定如何使用细胞来操纵生物膜相关的生长途径。在目标 2 中，我们将分析诱导溶原进入裂解阶段的机制杀死宿主而不将毒力因子传播到生物膜之外。在目标 3 中，我们强化了通过优化裂解噬菌体伏击任何逃脱的分散者来实现先前的目标。该提案的目标是开发一种创新的、多管齐下的噬菌体治疗方法生物膜相关细菌，同时还增加了对生物膜相关细菌的局限性和适用性的整体了解噬菌体疗法。