The impact of bacteriophage therapy on wound infection dynamics

噬菌体疗法对伤口感染动态的影响

• 批准号: 10467125
• 负责人: Daniel J Wozniak
• 金额: $ 76.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-02 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467125
• 关键词: Acinetobacter baumannii; Adjuvant; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Bacteriophages; Biological Models; Biology; Caring; Cells; Cessation of life; Characteristics; Complex; Defense Mechanisms; ESKAPE pathogens; Ecology; Ecosystem; Elements; Etiology; Evolution; Exudate; Family suidae; Foundations; Future; Healthcare Systems; Human; Immune response; Immunosuppression; In Vitro; Infection; Inflammatory; Injury; Knowledge; Lead; Liquid substance; Medical Care Costs; Metabolic; Microbial Biofilms; Morbidity - disease rate; Multi-Drug Resistance; Mus; Pathogenicity; Patients; Persons; Predisposition; Property; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Research; Resistance; Skin; Staphylococcus aureus; System; Therapeutic; Time; Toxic effect; Translating; Variant; Wound Infection; Wound models; aggressive therapy; antibiotic tolerance; antimicrobial resistant infection; bactericide; base; burn wound; chronic infection; chronic wound; commensal microbes; cytotoxicity; effective therapy; in vitro activity; in vivo; in vivo evaluation; infectious disease treatment; inflammatory milieu; microbial; microbiome; microbiota; mortality; multi-drug resistant pathogen; multidrug-resistant Pseudomonas aeruginosa; multiple omics; non-healing wounds; opportunistic pathogen; pathogen; preclinical study; prevent; programs; research clinical testing; response; standard of care; therapy development; translation to humans; wound; wound environment

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.

项目摘要 使用抗生素治疗生物膜相关感染可能受到病原体抗生素耐药性的限制，如 以及感染所表现出的抗生素耐受性。该应用程序旨在开发新的策略， 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，多样，毒性极小，特别是局部使用时， 对微生物组的影响可以忽略不计。由于有限的交叉耐药性， 倾向于保持噬菌体易感性，并且可以开发噬菌体混合物（polyurethane）以最小化抗性 从而更好地确保目标细菌的持续易感性。一个咄咄逼人的 细菌和生物膜破坏剂的混合物-抗生素和抗生素-可能 可用于减少抗肿瘤性和其它对治疗实验性伤口的挑战 感染.在这里，我们建议开发杀菌性细菌病毒（噬菌体或噬菌体） 作为抗生素应用的辅助剂，目的是在保持当前 护理标准。重点放在MDR铜绿假单胞菌感染和混合感染的治疗上。 伤口感染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 活性、对生物膜发挥作用的能力、宿主范围宽度（包括多药耐药和菌落变异） P.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。目的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， 体内测试鸡尾酒在复杂的多微生物感染，并将调查如何噬菌体治疗为基础的 病原体的靶向可引起伤口微生物群的变化。总的来说，这种疗法将用于 减少由多重耐药铜绿假单胞菌引起的毁灭性感染的负担。本研究还将 为针对每种主要ESKAPE病原体的计划奠定基础。