The Electricidal Effect, a Novel Anti-Biofilm Strategy

电效应，一种新型的抗生物膜策略

基本信息

批准号：
8637908
负责人：
Robin Patel
金额：
$ 39.43万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637908
关键词：
Adverse effects Animal Model Antibiotics Antimicrobial Resistance Antimicrobial susceptibility Bacteria Bacterial Adhesion Bacterial Infections Biocide Candida albicans Cells Chronic Clinical Communities Data Device Removal Devices Dose Enterococcus faecalis Escherichia coli Exposure to Failure Foreign Bodies Fracture Healing Host Defense Hour Human Implant In Vitro Infection Joints Laboratories Laboratory Study Medical Device Microbial Biofilms Modeling Organ Oryctolagus cuniculus Oxidative Stress Pharmaceutical Preparations Play Predisposition Prevention Preventive Production Propionibacterium acnes Prosthesis Pseudomonas aeruginosa Publishing Reactive Oxygen Species Refractory Resistance Role Safety Staphylococcus aureus Staphylococcus epidermidis Streptococcus mutans Surface Testing Therapeutic Time Tissues Toxic effect X-Ray Computed Tomography Yeasts antimicrobial antimicrobial drug bone bone strength catalase clinical practice experience fungus in vitro Model in vivo innovation killings microorganism novel prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Biofilm bacteria are estimated to cause two thirds of infections in modern clinical practice. In biofilms, microorganisms are protected from killing by innate host defenses and most available antimicrobial agents, culminating in the need for device removal in many device-associated infections (e.g., prosthetic joint infection). Given the failure of antimicrobics in the management of biofilm-associated device infections, a novel and innovative therapeutic and preventive non-antimicrobial approach is needed. Such a strategy would limit emergence of conventional antimicrobial resistance, as conventional antimicrobial agents would not be needed. Such a strategy would also limit toxicity associated with systemic antimicrobial agents. The preliminary in vitro studies described in our first submission demonstrated that electrical currents of 20 to 2000 <A substantially reduced established Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis biofilms, a phenomenon we termed the "electricidal effect" (Antimicrob Ag Chemother 2009;53:41). {Preliminary data generated with two new isolates each of P. aeruginosa, S. aureus, and S. epidermidis, three isolates each of Escherichia coli and Enterococcus faecalis, and single isolates of each of Streptococcus mutans species group and Candida albicans also demonstrate an electricidal effect.} We have shown that electrical current is active against S. epidermidis biofilms in a rabbit foreign body infection model (Antimicrob Ag Chemother 2009;53:4064). Notably, direct current has a precedent of being safely used in clinical practice (e.g., to accelerate fracture healing). We hypothesize that the electricidal effect is broadly active against a variety of bacterial and fungal biofilms (i.e., beyond those studied to date). We further hypothesize that electrical current will not only treat, but will also prevent biofilm formation, and that this strategy is safe. We will establish optimal in vitro and in vivo parameters to maximize the electricidal effect, and we will determine whether the observed killing of biofilm-associated P. aeruginosa, S. aureus, S. epidermidis, {E. coli, E. faecalis, S. mutans and C. albicans}, generalizes to other genera, species and strains of bacteria and fungi. {We will characterize adverse effects (if any) associated with delivery of electrical current in our animal model using functional (i.e., bone strength testing), whole organ (i.e., bone micro-computed tomography) and tissue (i.e., histomorphometry) assessments.} We will assess whether electrical current prevents bacterial adhesion to surfaces in vitro and in vivo. The mechanism that underlies this effect is unknown. We hypothesize that oxidative stress plays a role. {We have generated new preliminary data showing that, compared with wild-type bacteria, catalase-deficient bacteria have enhanced susceptibility to the electricidal effect, supporting our mechanistic hypothesis. If further studies do not support this hypothesis, we will evaluate detachment as a mechanism.} Results of this study are expected to provide a rationale and supporting data for the use of the electricidal effect for prevention and treatment of device-related bacterial infections in humans. This strategy has the potential to eliminate the need for device removal in human device-related infections. Not only will this approach be active against biofilms, but it will limit the emergence of resistance to conventional antimicrobial agents, resulting in less (futile) use of such drugs.

描述（由申请人提供）：在现代临床实践中，估计生物膜细菌引起三分之二的感染。在生物膜中，宿主先天防御和大多数可用的抗菌剂可以保护微生物免遭杀死，最终导致许多设备相关感染（例如假体关节感染）需要移除设备。鉴于抗菌药物在治疗生物膜相关设备感染方面的失败，需要一种新颖且创新的治疗和预防性非抗菌方法。这种策略将限制传统抗菌药物耐药性的出现，因为不需要传统抗菌药物。这种策略还将限制与全身抗菌剂相关的毒性。我们第一份提交文件中描述的初步体外研究表明，20 至 2000 <A 的电流可显着减少已建立的铜绿假单胞菌、金黄色葡萄球菌和表皮葡萄球菌生物膜，我们将这种现象称为“电效应”（Antimicrob Ag Chemother 2009；53）：41）。 {用铜绿假单胞菌、金黄色葡萄球菌和表皮葡萄球菌各两个新分离株，大肠杆菌和粪肠球菌各三个分离株，以及变形链球菌物种组和白色念珠菌各单个分离株产生的初步数据也证明了电性我们已经证明，电流对兔子异物感染中的表皮葡萄球菌生物膜具有活性模型（Antimicrob Ag Chemother 2009；53：4064）。值得注意的是，直流电有在临床实践中安全使用的先例（例如，加速骨折愈合）。我们假设电效应对多种细菌和真菌生物膜具有广泛的活性（即，超出了迄今为止研究的范围）。我们进一步假设电流不仅可以治疗，还可以防止生物膜的形成，并且这种策略是安全的。我们将建立最佳的体外和体内参数以最大化电效应，并且我们将确定是否观察到对生物膜相关的铜绿假单胞菌、金黄色葡萄球菌、表皮葡萄球菌、{E.大肠杆菌、粪肠球菌、变形链球菌和白色念珠菌}，可推广到细菌和真菌的其他属、种和菌株。 {我们将使用功能（即骨强度测试）、整个器官（即骨微计算机断层扫描）和组织（即组织形态计量学）评估来描述与动物模型中电流传递相关的不良影响（如果有）。我们将评估电流是否可以防止细菌在体外和体内粘附到表面。这种效应背后的机制尚不清楚。我们假设氧化应激发挥了作用。 {我们生成的新初步数据表明，与野生型细菌相比，过氧化氢酶缺陷细菌对电效应的敏感性增强，支持了我们的机制假设。如果进一步的研究不支持这一假设，我们将评估分离作为一种机制。}这项研究的结果预计将为利用电效应预防和治疗人类设备相关细菌感染提供理论依据和支持数据。该策略有可能消除人类设备相关感染中移除设备的需要。这种方法不仅可以有效对抗生物膜，而且可以限制传统抗菌药物耐药性的出现，从而减少此类药物的使用（徒劳）。