Project 1

抽象的。金黄色葡萄球菌是一种革兰氏阳性细菌，临床上以新分离的菌株为主。 出现了表现出抗药性的药物，使目前的药物武器库的治疗具有挑战性。金黄色葡萄球菌 最常见的多药耐药(MDR)病原体，通常被称为“超级细菌”， 其中以耐甲氧西林金黄色葡萄球菌(MRSA)最为突出。耐甲氧西林金黄色葡萄球菌不再局限于医疗医院 并在人与人之间迅速传播。随着问题的日益严重，人们对有效的 治疗，导致对新的抗菌剂的强烈需求。 以秀丽隐杆线虫为感染模型，我们进行了高通量筛查 鉴定具有抗金黄色葡萄球菌活性的化合物，特别是MRSA。我们的调查确定了反- 炎性化合物金诺芬(FDA批准的药物)和草药提取物紫草素能够 提高感染线虫的存活率，在0.25g/ml和4g/ml表现出最低抑制浓度， 分别进行了分析。为了适应我们对金诺芬和紫草素作为潜在的新抗菌剂的研究 抗金黄色葡萄球菌的化合物，我们将询问金诺芬的分子靶点，考察其对金黄色葡萄球菌的影响 硫氧还蛋白系统，许多革兰氏阳性细菌的基本抗氧化防御系统。我们的考试将会 包括对临床分离株和低剂量暴露于这些化合物调查，以确定细菌是否具有 现有的抗药性机制或可能产生抗药性(目标1)。 我们的目的是研究TrxR靶向化合物在小鼠体内的翻译 作为金黄色葡萄球菌的感染模型。我们将确定我们的TrxR靶向化合物对S。 金黄色葡萄球菌抑制，评估全身和局部感染(目标2)。进一步，构建一类新的硫氧还蛋白 系统抑制性抗生素，我们将进行抗菌素靶标筛选，以确定新的化合物， 增加我们找到可药物化合物的机会(目标3)。从而推动了对奥拉诺芬的调查， 紫草素和其他TrxR抑制化合物可能被用作特定细菌感染的治疗选择。

Abstract. Staphylococcus aureus is a Gram-positive bacterium that is clinically prominent with new isolates emerging that exhibit drug resistance, making treatments challenging with the current drug arsenal. S. aureus is the most commonly recognized multi-drug resistant (MDR) pathogen and it often referred to as a “superbug”, methicillin resistant S. aureus (MRSA) being the most prominent. MRSA is no longer limited to medical hospitals and are rapidly transmitted from person to person. With the growing problem, there is concern about effective treatment, leading to a fervent need for new antimicrobials. Using Caenorhabditis elegans as an infection model, we performed a high throughput screen (HTS) to identify compounds with activity against S. aureus, particularly MRSA. Our investigation determined that the anti- inflammatory compound auranofin (an FDA approved drug) and the medicinal herb extract shikonin are able to improve survival of infected nematodes, exhibiting minimal inhibitory concentrations at 0.25 g/ml and 4 g/ml, respectively. To accommodate our investigations of auranofin and shikonin as potential new antimicrobial compounds against S. aureus, we will interrogate the molecular target of auranofin, examining the effects to the thioredoxin system, an essential antioxidant defense in many Gram-positive bacteria. Our examination will include a survey of clinical isolates and low dose exposure to these compounds to determine if bacteria have available resistance mechanisms or can develop resistance (aim 1). Our aim is to investigate the translation of TrxR targeted compounds to mammalian systems using mice as an infection model for S. aureus. We will determine the drug efficacy of our TrxR targeted compounds on S. aureus inhibition, evaluating systemic and local infections (aim 2). Further, to build a new class of thioredoxin system inhibitory antibiotics, we will engage an antibatcerial target specific screen to identify new compounds, enhancing our chances of finding a drugable compound (aim 3). Thus driving the investigation of auranofin, shikonin, and other TrxR inhibitory compounds toward use as a treatment option for specific bacterial infections.