THERAPEUTIC APPROACHES TO BIOFILM ANTIBIOTIC RESISTANCE

描述（由申请方提供）：表皮葡萄球菌和金黄色葡萄球菌是留置器械相关感染的主要原因，在美国每年影响多达400，000例患者。在体内，这些病原体在医疗植入物上形成生物膜，这些生物膜对抗生素具有内在抗性，并受到免疫系统的攻击。 我们的总体目标是开发专门针对生物膜生长模式的药物。这代表了对现有抗生素疗法的创新，现有抗生素疗法靶向嗜热菌，并且不能有效根除生物膜细菌。我们的策略是筛选小分子化合物，降低葡萄球菌生物膜对抗生素的内在耐药性。这些化合物将使生物膜细菌对临床使用的抗生素敏感。在第一阶段，我们将确定和验证小分子药物发现的基因靶点。 具体目标如下：目标1。开发高通量筛选，用于鉴定生物膜中内在抗生素抗性缺陷的突变体。目标2.识别S。表皮突变体在生物膜中的内在抗生素抗性缺陷。目标3.在一组体外试验中评估突变体，鉴定转座子插入位点，并为靶点验证研究确定突变体的优先级。目标4。在Aim 2和Aim 3中鉴定出作为小分子药物发现的潜在靶点的p53基因。在第二阶段，我们将开发验证目标的筛选，并使用它们来鉴定使葡萄球菌生物膜对抗生素敏感的化合物。 我们将把这些化合物开发成创新药物，与临床相关的抗生素联合使用，以根除生物膜感染。

DESCRIPTION (provided by applicant): Staphylococcus epidermidis and Staphylococcus aureus are the leading causes of indwelling-device related infections, affecting up to 400,000 patients/year in the United States. In the body, these pathogens form biofilms on medical implants that are intrinsically resistant to antibiotics and attack by the immune system. Our overall goal is to develop drugs that specifically target the biofilm mode of growth. This represents an innovation over existing antibiotic therapies that target planktonic bacteria and are not effective in eradicating biofilm bacteria. Our strategy is to screen for small molecule compounds that reduce the intrinsic resistance of Staphylococcal biofilms to antibiotics. These compounds will sensitize biofilm bacteria to antibiotics that are in clinical use. In Phase I, we will identify and validate gene targets for small molecule drug discovery. The specific aims are as follows: Aim 1. Develop a high-throughput screen for identifying mutants defective in intrinsic antibiotic resistance in biofilms. Aim 2. Identify S. epidermidis mutants defective in intrinsic antibiotic resistance in biofilms. Aim 3. Evaluate mutants in a panel of in vitro assays, identify transposon insertion sites, and prioritize mutants for target validation studies. Aim 4. Validate genes identified in Aim 2 and Aim 3 as potential targets for small molecule drug discovery. In Phase II, we will develop screens for validated targets and use them to identify compounds that sensitize Staphylococcal biofilms to antibiotics. We will develop these compounds into innovative drugs that will be used in combination with clinically relevant antibiotics to eradicate biofilm infections.