The impact of bacteriophage therapy on wound infection dynamics

项目摘要 使用抗生素治疗生物被膜相关感染可能受到病原体抗生素耐药性的限制，如 以及感染表现出的抗生素耐受性。此应用程序寻求开发新的战略，以 消除由多重耐药病原体引起的持续性伤口感染。噬菌体是天然的， 丰富的，种类繁多，毒性最小，特别是当局部使用时，并假设有 对微生物群的影响可以忽略不计。由于有限的交叉耐药性，表现出抗生素耐药性的细菌 倾向于保持对噬菌体的敏感性，并且可以开发噬菌体鸡尾酒(多噬菌体)来最小化耐药性 与多个噬菌体结合，从而更好地确保目标细菌的持续敏感性。因此，一个具有侵略性的 细菌和生物被膜干扰剂的混合物-噬菌体和抗生素-可能 用于减少抗生素耐药性和其他具有挑战性的治疗实验伤口 感染。在这里，我们建议开发杀菌细菌病毒(噬菌体或噬菌体) 作为抗生素应用的辅助剂，目的是在保持现有技术的同时，进行未来的临床试验 护理标准。重点治疗耐多药铜绿假单胞菌感染和混合感染。 感染的伤口。我们开发的用于治疗的五个关键噬菌体特征是强大的抗菌素 活性、对生物膜起作用的能力、寄主范围的广度，包括多药耐药性和菌落变异 铜绿假单胞菌，对宿主细胞的有限细胞毒性，以及噬菌体稳定性。目标1将评估噬菌体鸡尾酒 单微生物和多微生物模型系统中的治疗。AIM 2利用生态系统生物学方法 鸡尾酒在复杂的多菌感染中的活体测试，并将调查基于噬菌体疗法的 以病原体为靶标可能会引起伤口微生物区系的变化。总体而言，这种疗法将用于 减轻多重耐药铜绿假单胞菌引起的破坏性感染的负担。这项研究还将 为针对每一种主要ESKAPE病原体的计划奠定基础。

Project Abstract Treatment of biofilm-associated infections using antibiotics can be limited by pathogen antibiotic resistance, as well as antibiotic tolerance displayed by infections. This application seeks to develop new strategies to eliminate persistent wound infections caused by multidrug resistant pathogens. Bacteriophages are natural, abundant, and diverse with minimal toxicity, particularly when used topically, and assumed to have negligible impact on the microbiome. Due to limited cross-resistance, bacteria displaying antibiotic resistance tend to remain phage susceptible and phage cocktails (polyphages) can be developed to minimize resistance to multiple phages, thereby better assuring continued susceptibility of targeted bacteria. Thus, an aggressive mixture of bacteria- and biofilm-disrupting agents – phages and antibiotics – may be employed towards reducing antibiotic-resisting and otherwise challenging-to-treat experimental wound infections. Here we propose to develop bactericidal bacterial viruses (bacteriophages or phages) as adjuvants to antibiotic application, with an aim towards future clinical testing while retaining current standards of care. Emphasis is placed on the treatment of MDR Pseudomonas aeruginosa-infected and mixed- infected wounds. The five key phage characteristics that we developed for therapy are robust antibacterial activity, ability to function against biofilms, host range breadth including multidrug resistant and colony variant P. aeruginosa, limited cytotoxicity against host cells, and phage stability. Aim 1 will evaluate the phage cocktail therapy in mono- and poly-microbial model systems. Aim 2 utilizes eco-systems biology approaches for in vivo testing of cocktails in a complex polymicrobial infection and will investigate how phage therapy-based targeting of a pathogen may cause changes to the wound microbiota. Overall, such therapy will be used to reduce the burden of devastating infections caused by multidrug resistant P. aeruginosa. This study will also lay the foundation for a program targeting each of the major ESKAPE pathogens.