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：
8456999
负责人：
Robin Patel
金额：
$ 37.03万
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/8456999
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）：估计生物膜细菌在现代临床实践中引起三分之二的感染。在生物膜中，微生物免受先天宿主防御和大多数可用的抗微生物剂的杀戮保护，最终导致许多与设备相关的感染（例如，假体关节感染）中需要去除装置。鉴于抗菌药物在生物膜相关的装置感染中的管理中失败，需要一种新颖而创新的治疗性和预防性的非抗菌方法。这种策略将限制常规抗菌耐药性的出现，因为不需要常规的抗菌剂。这种策略还将限制与全身性抗菌剂有关的毒性。初步的体外研究在我们的第一次意见中描述的是，20至2000年的电流大大降低了已建立的铜绿假单胞菌，金黄色葡萄球菌和葡萄球菌表皮生物膜生物膜，我们称为“电效效应”（AntimicoB ob ag ag ag ag ag ag ag ag ag ag ag ag ag obiCoB obs 2009）。 {用两个新的分离株生成的初步数据，每个分离株，金黄色葡萄球菌和链球菌，三个分离物，每个分离e Escherichia coli and entocococcus Faecalis，单个分离株，链球菌Mutans Mutans群和念珠菌的每个分离物也表明了EPRIB的电气效应。外国体内感染模型（Antimicrob AG Chemother 2009; 53：4064）。值得注意的是，直流电流具有安全用于临床实践（例如，加速骨折愈合）的先例。我们假设电效效应对各种细菌和真菌生物膜（即，超出迄今为止研究的细菌）广泛活跃。我们进一步假设电流不仅可以治疗，而且还将防止生物膜形成，并且该策略是安全的。我们将建立最佳的体外和体内参数，以最大化电效应，并确定观察到的生物膜相关的铜绿假单胞菌，S。Aureus，S。eureus，S。epidermidis，{E。大肠杆菌，E。Faecalis，S。Mutans和C. albicans}概括到其他属，物种和菌株和真菌的属。 {我们将使用功能（即骨骼强度测试），整个器官（即骨微型计算层析成像）和组织（即组织形态测定）评估（即，骨骼强度测试）的功能（即骨骼强度测试）来表征与我们动物模型中电流传递相关的不利影响（如果有）。构成这种效果的机制尚不清楚。我们假设氧化应激起着作用。 {我们已经生成了新的初步数据，该数据表明，与野生型细菌相比，过氧化氢酶缺陷型细菌具有增强的电效应敏感性，从而支持我们的机械假设。如果进一步的研究不支持这一假设，我们将评估脱离作为一种机制。}这项研究的结果有望为使用电力效应提供基本原理和支持数据，以预防和治疗人类中与器械相关的细菌感染。该策略有可能消除与人体设备相关感染中拆卸设备的需求。这种方法不仅会对生物膜有效，而且会限制对常规抗菌剂的抗性的出现，从而减少了这种药物的使用（徒劳）。