Antibiotic-binding Peptides for Biofilm Prevention on Ventriculoperitoneal Shunts

描述(申请人提供)：脑室-腹膜分流术(VP)用于治疗重症儿童和新生儿脑积水，约占受影响婴儿的1/3。由于易受感染和机械故障的影响，VP分流术的故障率约为30%~40%。因此，有必要改善对这一过程的感染预防，可能是通过减少微生物定植和随后在这些留置材料表面形成生物膜来实现的。分流管本身由一个塑料瓣膜组成，硅胶管从侧脑室通向良性区域，排空的脑脊液(CSF)可以在那里被重新吸收。大多数感染发生在植入后2个月内，并被归因于皮肤上的菌群。因此，内脏来源的感染并不典型。从外部引流脑脊液的脑室外引流(EVD)也显示出来自这些来源的类似感染率。目前预防感染的战略代表了一系列医疗实践和技术进步。全身应用抗生素通常用于围手术期，但据报道对感染率影响有限。使用抗生素浸渍材料局部预防微生物定植已成为一种令人兴奋的新预防策略，已被多项临床研究证实。该方案使用了一种新的抗菌方法，使用高亲和力的多肽涂层将抗生素非共价连接到VP分流管上。AffinEnergy已经开发了一系列能够结合植入的生物材料和治疗剂的多肽，我们称之为界面生物材料(IFBms)。在这个第一阶段的研究计划中，我们将尝试优化与VP分流管的硅胶管结合的多肽，并将该序列与我们已知的对抗万古霉素的抗生素结合肽结合起来。这种塑料：万古霉素IFBM将能够将万古霉素输送并保留在VP分流管的塑料管上，以防止感染。这项提议的成功完成将导致能够输送生物活性万古霉素的VP分流涂层原型。在临床上，我们的IFBM介导的给药方法有几个优势，包括：1)材料和药物结合模块可以互换，以实现新的治疗策略；2)多肽和抗生素的组合可以在分流管植入前几分钟应用于分流管；3)外科医生可以选择最适合患者的任何分流材料或一种以上的抗生素，而不是使用一种特定的抗生素治疗。这一第一阶段计划的成功完成将产生一种基于多肽的抗生素传递原型，为体内疗效和生物兼容性的第二阶段研究做好准备。公共卫生相关性：由于脑室腹膜分流术(VP)的感染率很高，因此迫切需要提高其抵御微生物定植的能力。虽然目前的策略包括用抗生素浸泡这些材料，但新的治疗方法有望允许医生在任何VP分流材料上应用他们选择的抗生素。AffinEnergy开发的涂层使用双功能、高亲和力的多肽将治疗分子附着到植入的材料表面。在本次研究中，我们将研制一种新的涂层，将万古霉素附着在硅胶VP分流管上。在这里，我们将开发多肽成分，组装双功能涂层分子，并在体外测试其抗菌效果。这一第一阶段计划的完成将产生一种基于多肽的抗生素传递原型，为体内疗效和生物兼容性的第二阶段研究做好准备。

DESCRIPTION (provided by applicant): Ventriculoperitoneal (VP) shunts are used to treat pediatric and neonatal hydrocephalus in severe cases, representing approximately 1/3rd of affected infants. Due to the high susceptibility for infection and mechanical breakdown, the failure rate of VP shunts is around 30-40%. A need therefore exists to improve infection prevention for this procedure, likely by reducing microbial colonization and subsequent biofilm formation on the surface of these indwelling materials. The shunt itself is composed of a plastic valve, with silicone tubing leading from the lateral ventricle to a benign region where evacuated cerebrospinal fluid (CSF) can be reabsorbed. The majority of infection occurs within 2 months of implantation, and has been attributed to skin-dwelling flora. Therefore viscerally-derived infections are not typical. External ventricular drains (EVDs), which drain CSF externally, also exhibit similar infection rates from these sources. Current strategies to prevent infections represent a range of medical practices and technological advances. Systemic antibiotic administration is commonly used perioperatively but has been reported to exert a limited effect on infection rates. Using antibiotic impregnated materials for localized prevention of microbial colonization has become an exciting new prevention strategy validated through several clinical studies. The proposal here uses a novel antimicrobial approach, using high affinity peptide coatings to attach antibiotics noncovalently to VP shunt tubing. Affinergy has developed a range of peptides capable of binding implanted biomaterials, and therapeutic agents which we have termed interfacial biomaterials (IFBMs). During this Phase I research program we will attempt to optimize peptides which bind to the silicone tubing of a VP shunt, and combine this sequence with our known antibiotic-binding peptides against vancomycin. This plastic: vancomycin IFBM will be capable of delivering and retaining vancomycin on the plastic tubing of a VP shunt to prevent infection. Successful completion of this proposal will result in a prototype VP shunt coating capable of delivering bioactive vancomycin. Clinically, our IFBM-mediated delivery approach has several advantages including: 1) material and drug-binding modules can be interchanged for new therapeutic strategies; 2) peptide and antibiotic combinations can be applied to shunts at point-of-care, minutes before their implantation and 3) surgeons can choose any shunting materials or more than one class of antibiotics that best suit the patient rather than having one particular product with the antibiotic treatment. Successful completion of this Phase I program will result in a peptide-based antibiotic delivery prototype, ready for Phase II studies of in vivo efficacy and biocompatibility. PUBLIC HEALTH RELEVANCE: Because ventriculoperitoneal (VP) shunts exhibit a high rate of infection, there exists a strong need to enhance their ability to withstand microbial colonization. While current strategies involve impregnating these materials with antibiotics, new treatments will hopefully allow physicians to apply their choice of antibiotic on any VP shunt material. The coatings developed by Affinergy employ bifunctional, high-affinity peptides to attach therapeutic molecules to an implanted material surface. During this research program, we will generate a new coating, which attaches vancomycin to silicone VP shunts. Here, we will develop the peptide components, assemble the bifunctional coating molecules and test its antimicrobial efficacy in vitro. Completion of this Phase I program will result in a peptide-based antibiotic delivery prototype, ready for Phase II studies of in vivo efficacy and biocompatibility.