Novel Inhibitors of Staphylococcal Biofilm Formation

描述（由申请方提供）：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400，000名患者。为了解决这一未满足的医疗需求，我们正在开发特异性抑制葡萄球菌生物膜形成的小分子。这些新药将被用作中心静脉导管等留置医疗器械的涂层，以防止葡萄球菌生物膜感染。在之前的第二阶段SBIR资助中，我们鉴定了一类小分子，称为绕丹宁，是体外葡萄球菌生物膜形成的有效抑制剂。在SBIR的第一阶段，我们将优化罗丹宁生物膜抑制剂以产生先导化合物。将使用体外和体内试验中的重复合成和评价来探索该化学类别的结构活性关系，并提高效价和选择性。符合体外抗生物膜效力（MBIC = 0.1 μ M）、特异性（MIC/MBIC = 500）和选择性（CC 50/MBIC = 50）规定标准的化合物将用于作用机制（MOA）研究和体内毒性和疗效测定。具有经验证的MOA、体内功效和可接受的体内毒性（MTD<1 mg/kg）的化合物将被指定为先导化合物。在第二阶段，先导化合物将使用合理的药物设计进行优化。第一阶段提案的具体目标如下。目标1。设计和合成具有改善的抗生物膜活性的绕丹宁类似物。目标2.优化生物膜形成的新型抑制剂的体外抗生物膜活性、光谱和选择性。目标3。测定浸渍有抗生物膜化合物的导管材料的体外抗生物膜活性。目标4。确定优化化合物的作用机制（MOA）。目标5。在生物膜感染的体内模型中确定先导化合物的急性毒性和功效。 该提案的目标是开发药物，用于医疗器械上的涂层，以防止葡萄球菌生物膜形成。这一点很重要，因为表皮葡萄球菌和金黄色葡萄球菌是导致绝大多数与使用留置医疗器械相关的生物膜相关感染的原因。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。在生物膜中生长的细菌对抗生素、杀生物剂和人体免疫系统的攻击具有高度抗性。因此，生物膜感染难以根除，并导致复发性血流感染。该提案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.