Novel Inhibitors of Staphylococcal Biofilm Formation

描述(由申请人提供)：由表皮葡萄球菌和金黄色葡萄球菌引起的生物膜相关感染构成了重大的医学挑战。它们是医院获得性感染的主要原因，在美国每年影响多达40万名患者。为了解决这一未得到满足的医疗需求，我们正在开发专门抑制葡萄球菌生物膜形成的小分子。这些新型药物将用于中心静脉导管等留置医疗设备的涂层，以防止葡萄球菌生物被膜感染。在之前的第二阶段SBIR拨款中，我们确定了一类被称为罗丹宁的小分子，它们是体外葡萄球菌生物被膜形成的有效抑制剂。在这项SBIR的第一阶段，我们将优化罗丹宁生物膜抑制剂，以产生一种先导化合物。我们将在体外和体内反复进行合成和评价，以探索这类化合物的结构和活性关系，并提高其效力和选择性。符合体外抗生物被膜效力(MBIC=0.1M)、特异性(MIC/MBIC=500)和选择性(CC50/MBIC=50)的特定标准的化合物将进入作用机制(MOA)研究和体内毒性和有效性测试。具有经过验证的MOA、体内有效性和可接受的体内毒性(MTD&lt；1 mg/kg)的化合物将被指定为先导化合物。在第二阶段，将使用合理的药物设计来优化先导化合物。这项第一阶段提案的具体目标如下。目的1.设计合成具有抗生物被膜活性的罗丹宁类似物。目的2.优化新型生物被膜形成抑制剂的体外抗生物被膜活性、光谱和选择性。目的3.测定含抗生物被膜化合物的导管材料的体外抗生物被膜活性。目的4.确定优化化合物的作用机理。目的5.在体内生物被膜感染模型中测定铅化合物的急性毒性和有效性。 这项提案的目标是开发用于医疗器械涂层的药物，以防止葡萄球菌生物膜的形成。这一点很重要，因为与使用留置医疗器械相关的生物被膜感染的绝大多数是表皮葡萄球菌和金黄色葡萄球菌所致。葡萄球菌病原体能够在人体内的医疗器械表面定植并形成生物膜，这代表了一种独特的表面附着生长模式。生长在生物膜中的细菌对抗生素、杀生剂和人体免疫系统的攻击具有高度的抵抗力。因此，生物被膜感染很难根除，并导致反复发生的血液感染。这一提议的创新之处在于开发专门针对生物膜生长模式的药物，以预防生物膜相关感染。

DESCRIPTION (provided by applicant): Biofilm-related infections caused by Staphylococcus epidermidis and Staphylococcus aureus pose significant medical challenges. They are the leading cause of hospital-acquired infections, affecting up to 400,000 patients/year in the United States. In order to address this unmet medical need, we are developing small molecules that specifically inhibit staphylococcal biofilm formation. These novel drugs will be used as coatings for indwelling medical devices, such as central venous catheters, to prevent staphylococcal biofilm infections. In a previous Phase II SBIR grant, we identified a class of small molecules, known as the rhodanines, that are potent inhibitors of in vitro staphylococcal biofilm formation. In Phase I of this SBIR, we will optimize the rhodanine biofilm inhibitors for the generation of a Lead compound. Repeated rounds of synthesis and evaluation in in vitro and in vivo assays will be used to explore the structure activity relationships of this chemical class and to improve potency and selectivity. Compounds that meet the specified criteria for anti-biofilm potency in vitro (MBIC = 0.1 ¿M), specificity (MIC/MBIC = 500), and selectivity (CC50/MBIC = 50) will be advanced to mechanism of action (MOA) studies and in vivo assays for toxicity and efficacy. Compounds with verified MOA, in vivo efficacy, and acceptable in vivo toxicity (MTD<1mg/kg) will be designated as Lead compounds. In Phase II, Lead compounds will be optimized using rational drug design. The Specific Aims for this Phase I proposal are as follows. Aim 1. Design and synthesize rhodanine analogs with improved anti-biofilm activity. Aim 2. Optimize in vitro anti-biofilm activity, spectrum, and selectivity of novel inhibitors of biofilm formation. Aim 3. Determine in vitro anti- biofilm activity of catheter material impregnated with anti-biofilm compounds. Aim 4. Determine mechanism of action (MOA) of optimized compounds. Aim 5. Determine acute toxicity and efficacy of lead compounds in an in vivo model for biofilm infection. The goal of this proposal is to develop drugs that will be used as coatings on medical devices that prevent staphylococcal biofilm formation. This is important because Staphylococcus epidermidis and Staphylococcus aureus are responsible for the vast majority of biofilm-related infections associated with the use of indwelling medical devices. Staphylococcal pathogens are able to colonize the surfaces of medical devices in the human body and form biofilms, which represents a unique mode of surface-attached growth. Bacteria growing in biofilms are highly resistant to antibiotics, biocides, and attack by the body's immune system. As a result, biofilm infections are difficult to eradicate and lead to recurrent bloodstream infections. The innovation of this proposal is to develop drugs that specifically target the biofilm mode of growth to prevent biofilm-related infections.