Novel Compounds from Sycamore Leaves for the Treatment of MRSA

 描述(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，可导致患者死亡和延长住院时间，从而导致更高的医疗费用。目前，全世界超过50%的葡萄球菌病例是由MRSA引起的。近年来，耐甲氧西林金黄色葡萄球菌已演变为对青霉素、万古霉素、四环素、红霉素等多种抗生素均可耐药的耐药株。因此，它们有时被称为“超级细菌”。近年来，这些“超级细菌”已成为严重威胁公众健康的疾病。由于MRSA相关感染的增加，特别是在医院，迫切需要有效和新的抗生素疗法。在初步研究中，我们从美洲悬铃木中分离到一个新的化合物，山奈酚3-O-α-L-(2“，3”-二对香豆酰)鼠李糖苷(KCR)，在体内外对MRSA和VRSA(万古霉素耐药金黄色葡萄球菌)都有抑制作用。美国农业部将梧桐树材料归类为一般认为是安全的(GRAS)，因为这种植物在传统民间医药和造纸业等领域有广泛的人类接触和使用。这些抗MRSA化合物的活性代谢物可能具有不同的作用机制，因为它们不显示出与现有抗生素的交叉耐药性或结构同源性。在这项计划中，我们计划通过动物模型和微生物学技术进一步研究这些高度选择性的抗MRSA KCR(铂)苷，包括最大耐受量(MTD)、治疗效果、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一流的新抗生素，具有新的作用机制，并为美国经济发展提供了独特的机会。此外，该项目的成功将解决目前控制MRSA和其他耐药葡萄球菌感染(如VRSA)的疗法的局限性。

 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.