The impact of bacteriophage therapy on wound infection dynamics

项目摘要 使用抗生素治疗生物膜相关感染可能会受到病原体抗生素耐药性的限制，因为 以及感染所表现出的抗生素耐受性。该应用程序旨在制定新策略 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， 丰富且多样，毒性最小，特别是局部使用时，并且被认为具有 对微生物组的影响可以忽略不计。由于有限的交叉耐药性，细菌表现出抗生素耐药性 倾向于保持噬菌体敏感性，并且可以开发噬菌体混合物（多噬菌体）以最大程度地减少耐药性 针对多种噬菌体，从而更好地确保目标细菌的持续敏感性。因此，一个激进的 细菌和生物膜破坏剂（噬菌体和抗生素）的混合物可能 用于减少抗生素耐药性和其他难以治疗的实验伤口 感染。在这里我们建议开发杀菌细菌病毒（噬菌体或噬菌体） 作为抗生素应用的佐剂，旨在未来的临床测试，同时保留当前的 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。我们为治疗开发的五个关键噬菌体特征是强大的抗菌作用 活性、对抗生物膜的能力、宿主范围广度，包括多重耐药性和菌落变异 铜绿假单胞菌，对宿主细胞的有限细胞毒性和噬菌体稳定性。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。目标 2 利用生态系统生物学方法 对复杂的多微生物感染中的鸡尾酒进行体内测试，并将研究基于噬菌体疗法的效果如何 针对病原体可能会导致伤口微生物群发生变化。总的来说，这种疗法将用于 减轻由多重耐药铜绿假单胞菌引起的毁灭性感染的负担。这项研究还将 为针对每种主要 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.