A NOVEL BIS-INDOLE COMPOUND AGAINST CATHETER COLONIZATION

描述(由申请人提供)：与医疗器械相关的感染可能是严重的，甚至是致命的。导管定植和植入后不久导管表面产生生物膜通常是感染的前奏。已经开发了许多抗菌治疗的导管来对抗这些感染，然而，其中许多临床疗效有限。因此，预防导管相关性感染仍然是一个主要的未得到满足的医疗需求。为了解决这个问题，我们开发了一种创新的导管涂层，已经被证明在防止革兰氏阳性和革兰氏阴性病原体的导管定植方面是有效的。这种创新的导管涂层由MBX-1631组成，这是一种由MicroBiotix公司开发的新型广谱抗菌剂。拟议研究的总体目标是开发用于医疗设备的抗菌涂层，以防止设备相关感染。在第一阶段，我们将配制含有MBX-1631和几种类似物的设备涂层，并将它们用于医疗设备材料的涂层。这些涂层设备的抗生物被膜性能和细胞毒性将在一系列体外测试中进行测试，以评估其有效性和选择性。此外，还将评估涂层装置的几个物理参数，如洗脱动力学和耐久性。最后，选定的涂层设备将在动物模型中进行评估，以测试其抗菌效果和毒性。在第二阶段，我们将进一步开发符合特定疗效、选择性和物理性能标准的化合物。在第一阶段，我们将完成以下具体目标：目标1.研制和应用由MBX-1631和几种类似物组成的导管涂层；目标2.通过体外分析评估涂层材料在防止细菌定植、选择性和物理性能方面的有效性；目标3.在异物感染和急性毒性动物模型中评价涂层材料的有效性和选择性。 公共卫生相关性：每年有500多万根血管导管被插入患者体内，其中约5%会导致导管相关性感染。细菌病原体在导管植入后不久就会在导管表面产生生物膜，是导管相关感染的原因。已经开发了一些经过抗菌处理的导管来对抗这些感染；然而，其中许多对生物被膜无效。为了解决这个问题，我们将开发一种创新的导管涂层，该涂层已被证明在防止革兰氏阳性和革兰氏阴性病原体的导管定植方面有效。

DESCRIPTION (provided by applicant): Infections associated with medical devices can be serious and even fatal. Catheter colonization and production of a biofilm on the surface of a catheter shortly after implantation are normally the prelude for infections. A number of antimicrobial-treated catheters have been developed to combat these infections, however, many of them have limited clinical efficacy. Thus, the prevention of catheter-associated infections remains a major unmet medical need. To combat this problem, we have developed an innovative catheter coating that has been shown to be effective in preventing catheter colonization by Gram-positive and Gram-negative pathogens. The innovative catheter coating consists of MBX-1631, a novel broad-spectrum antimicrobial agent that was developed by Microbiotix, Inc. The overall goal of the proposed research is to develop antimicrobial coatings for medical devices that will prevent device-associated infections. In Phase I, we will formulate device coatings containing MBX-1631 and several analogs, and we will use them to coat medical device materials. The anti-biofilm properties and cytotoxicity of these coated devices will be tested in a series of in-vitro assays to evaluate their efficacy and selectivity. In addition, the several physical parameters of the coated devices, such as elution kinetics and durability, will be evaluated. Finally, selected coated devices will be evaluated in animal models to test for their antimicrobial efficacy and toxicity. Compounds that meet specified criteria for efficacy, selectivity, and physical properties will be developed further in Phase II. In Phase I we will accomplish the following specific aims: Aim 1. Formulate and apply catheter coatings consisting of MBX-1631 and several analogs; Aim 2. Evaluate the efficacy in preventing bacterial colonization, selectivity, and physical properties of coated materials using in-vitro assays; Aim 3. Evaluate efficacy and selectivity of coated materials in animal models of foreign body infection and acute toxicity. PUBLIC HEALTH RELEVANCE: Over 5 million vascular catheters are inserted in patients every year, and about 5% of these catheters lead to catheter-associated infections. Bacterial pathogens that colonize catheters and produce a biofilm on the surface of the catheter shortly after implantation are the cause of catheter-associated infections. A number of antimicrobial-treated catheters have been developed to combat these infections; however, many of them are not effective against biofilms. To combat this problem, we will develop an innovative catheter coating that has been shown to be effective in preventing catheter colonization by Gram-positive and Gram-negative pathogens.