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甚至致命的。导管定植和导管表面生物膜的产生通常是感染的前奏。已经开发了许多抗微生物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，预防导管相关感染仍然是一个未得到满足的主要医疗需求。为了解决这个问题，我们开发了一种创新的导管涂层，该涂层已被证明可有效防止革兰氏阳性和革兰氏阴性病原体在导管上定植。这种创新的导管涂层由MBX-1631组成，这是一种由Microbiotix， Inc.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器械的抗菌涂层，以防止器械相关感染。在第一阶段，我们将配制含有MBX-1631和几种类似物的器件涂层，我们将使用它们来涂覆医疗器械材料。这些涂层装置的抗生物膜特性和细胞毒性将在一系列体外试验中进行测试，以评估其有效性和选择性。此外，涂层器件的几个物理参数，如洗脱动力学和耐久性，将被评估。最后，选定的涂层装置将在动物模型中进行评估，以测试其抗菌功效和毒性。符合功效、选择性和物理性质的特定标准的化合物将在第二阶段进一步开发。在第一阶段，我们将完成以下具体目标：目标一。配制和应用由MBX-1631和几种类似物组成的导管涂层；目标2。使用体外测定法评估涂层材料在防止细菌定植、选择性和物理特性方面的功效；目标3。评价包被材料在体外感染和急性毒性动物模型中的有效性和选择性。

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.