Novel Compounds from Sycamore Leaves for the Treatment of MRSA

 描述（由申请人提供）：耐甲氧西林金黄色葡萄球菌（MRSA）是一种严重的病原体，可导致患者死亡并延长住院时间，导致医疗保健费用增加。目前，世界上超过50%的葡萄球菌病例是由MRSA引起的。近年来，MRSA已演变成几种耐药菌株，可对青霉素、万古霉素、四环素和红霉素等多种抗生素产生耐药性。因此，它们有时被称为“超级细菌”。近年来，这些“超级细菌”已成为对公众健康的严重威胁。由于MRSA相关感染的不断增加，特别是在医院中，迫切需要有效和新颖的抗生素治疗。在初步研究中，我们从美国西卡莫尔（Platanus oceanentalis）中分离到一种新的化合物，山奈酚3-O-α-L-（2”，3”-二-p-香豆酰基）鼠李糖苷（KCR），其在体外和体内具有抗MRSA和VRSA（万古霉素抗性金黄色葡萄球菌）的活性。西卡莫尔材料已被美国农业部归类为一般认为安全的（GRAS），因为人类广泛接触和使用这种植物的传统民间医药和造纸工业，等等。这些抗MRSA化合物的活性代谢物可能具有独特的作用机制，因为它们不显示与已建立的抗生素的交叉耐药性或结构同源性。在本研究中，我们计划利用动物模型和微生物学技术进一步研究这些高选择性抗MRSA KCR（Platanosides），包括最大耐受剂量（MTD）、治疗功效、药代动力学（PK）、作用机制和体内毒性。该项目显然有潜力产生具有新型作用机制的一流新抗生素，并为美国经济发展提供独特的机会。此外，该项目的成功将解决目前控制MRSA和其他耐药性葡萄球菌感染（如VRSA）的治疗方法的局限性。

 DESCRIPTION (provided by applicant): Methicillin-resistant staphylococcus aureus (MRSA) is a serious pathogen that can cause patient mortality and extend hospital stays, resulting in higher health care costs. Currently, over 50% of staph cases around the world are caused by MRSA. In recent years, MRSA has evolved into several resistant strains that can resist to multiple antibiotics such as penicillin, vancomycin, tetracycline and erythromycin. For this reason, they are sometimes called "superbugs." In recent years, these "superbugs" have become a serious threat to public health. Because of the increasing presence of MRSA-related infections, especially in hospitals, there are urgent needs for effective and novel antibiotic therapies. In a preliminary study, we have isolated a novel compound, kaempferol 3-O-alpha-L-(2",3"-di-p-coumaroyl)rhamnoside (KCR) from the American sycamore (Platanus occidentalis) that were active against MRSA and VRSA (vancomycin resistant staphylococcus aureus) in vitro and in vivo. The sycamore materials have been classified by the USDA as generally regarded as safe (GRAS) because of extensive human contact and use of this plant in traditional folk medicines and paper industry, among others. Active metabolites of these anti-MRSA compounds likely possess a distinct mechanism of action as they do not show cross resistance or structural homology with established antibiotics. In this proposal, we plan to furthe investigate these highly selective anti-MRSA KCR (platanosides) including the maximum tolerated dose (MTD), therapeutic efficacy, pharmacokinetics (PK), mechanism of action, and in vivo toxicity using animal model and microbiological techniques. This project clearly has the potential to generate a first in class new antibiotic with a novel mechanism of action and provides a unique opportunity for US economic development. In addition, the success of this project will address the limitations of current therapies for the control of MRSA and other antibiotic-resistant staph infections such as VRSA.