Novel Strategies for Treating Biofilm-Forming Pathogens with Phage Therapy

项目摘要 日益严重的抗生素耐药性问题要求我们迫切地开发和测试新的方法 控制细菌感染。噬菌体疗法提供了巨大的前景，但意义重大 目前存在的知识差距限制了它们的应用。两个目前限制更广泛的 噬菌体疗法的使用是为每个感染挑选特定的裂解噬菌体菌株的问题，而 难以将噬菌体直接运送到需要它们的感染部位。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- 能够诱导常驻预言体的反应途径。通过分离这些细胞反应， 我们建议在稳定生物膜的同时诱导已经存在于细菌中的温带噬菌体。 基因组进入裂解期并杀死宿主细胞。通过这样做，我们有效地绕过了限制 通过寻找和递送匹配菌株的裂解噬菌体来感染，同时也发展 利用温带噬菌体疗法的方法。在目标1中，我们建议确定 生物膜扩散速度和确定生物膜相关生长如何通过细胞 小路。在目标2中，我们将分析溶原菌被诱导进入裂解相的机制 杀死它们的宿主，而不会将毒力因子扩散到生物膜之外。在目标3中，我们强调 用优化的裂解噬菌体埋伏任何逃逸的分散体来达到先前的目标。 这项提案的目标是开发一种创新的、多管齐下的方法来治疗 同时也增加了对生物膜相关细菌的限制和适用性的全面了解 噬菌体疗法。

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.