The impact of bacteriophage therapy on wound infection dynamics

噬菌体疗法对伤口感染动态的影响

基本信息

批准号：
10560606
负责人：
Daniel J Wozniak
金额：
$ 75.27万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10560606
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 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 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 care wound environment

项目摘要

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。该应用旨在开发新的策略来应对。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，并且被认为具有由于交叉耐药性有限，细菌表现出抗生素耐药性，对微生物组的影响可以忽略不计。往往保持噬菌体易感性，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多种噬菌体，从而更好地确保目标细菌的持续敏感性。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放在耐多药铜绿假单胞菌感染和混合感染的治疗上。我们为治疗而开发的五个关键噬菌体特征是强大的抗菌能力。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、针对宿主细胞的有限细胞毒性和噬菌体稳定性。目标 1 将评估噬菌体混合物。目标 2 利用生态系统生物学方法进行单一和多微生物模型系统的治疗。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总体而言，针对病原体可能会导致伤口微生物群发生变化。这项研究还将减轻多重耐药铜绿假单胞菌引起的毁灭性感染的负担。为针对每种主要 ESKAPE 病原体的计划奠定基础。