Strategies to Investigate Synergy in Botanical Medicines

描述（由申请人提供）：耐药细菌感染的问题已经达到流行病的程度。耐甲氧西林金黄色葡萄球菌（MRSA）感染现在每年杀死的美国公民比艾滋病多，治疗或预防这种感染的新策略是非常需要的。由于缺乏新的候选药物，以及细菌很快对新抗生素产生耐药性，这一问题变得更加复杂。在这个项目中，我们建议探索一种对抗细菌感染的替代策略，即使用含有多种不同作用模式的不同化合物的植物性药物。正在研究的植物是金毛（Hydrastis canadensis），它已在传统和现代替代医学中用于治疗感染。黄芪是一个重要的研究课题，因为它作为一种膳食补充剂很受欢迎（在美国最畅销的15种植物性药物中，在儿童最常用的药物中排名第六）。这种植物或其成分在许多体外和体内研究中显示出抗菌活性。我们强有力的初步数据为黄芪抗细菌的机制提供了新的见解。我们已经证明，这种植物含有多种生物活性成分，可以作为直接抗菌剂，作为外排泵抑制剂，以及作为抗毒化合物（通过群体猝灭）。此应用程序的主要目标是确定促成这些不同活动的组成部分。为了实现这一目标，我们将采用一种创新的方法，协同定向分馏，这是最近由首席研究员的实验室开发和发表的。我们的长期目标是利用这些研究提供的信息，使局部黄芪制剂的制备具有最佳疗效，以治疗或预防细菌感染。更广泛地说，我们还试图探索补充和替代医学的主要指导原则之一，即由于协同相互作用，多组分疗法的活性可以得到增强。作为本研究的一部分验证的方法有望证明对其他必须解释在许多植物性药物的活性中起作用的协同相互作用的研究人员有用。

DESCRIPTION (provided by applicant): The problem of drug-resistant bacterial infections has reached epidemic proportions. Methicillin-resistant Staphyolcoccus aureus (MRSA) infections now kill more US citizens each year than does AIDS, and new strategies to treat or prevent such infections are greatly needed. This issue is compounded by a lack of new drug candidates in the pipeline, and the fact that bacteria very quickly develop resistance to new antibiotics. With this project, we propose to explore an alternative strategy for combating bacterial infections, the use of a botanical medicine containing multiple different compounds with diverse modes of action. The botanical under investigation is goldenseal (Hydrastis canadensis), which has been used in traditional and modern alternative medicine to treat infections. Goldenseal is a significant topic of study because of its popularity as a dietary supplement (among the top 15 best-selling botanical medicines in the US, and the 6th most commonly used by children). This plant or its constituents have demonstrated antimicrobial activity in numerous in vitro and several in vivo studies. Our strong preliminary data provide new insights into the mechanisms by which goldenseal acts against bacteria. We have shown that this plant contains a diverse array of bioactive constituents, which can act as direct antimicrobia agents, as efflux pump inhibitors, and as anti-virulence compounds (via quorum quenching). A major goal of this application is to identify the constituents that contribute to these diverse activities. To accomplish this, we will employ an innovative approach, synergy-directed fractionation, which has recently been developed and published by the principal investigator's laboratory. Our long term objective is to use the information provided by these studies to enable the preparation of topical goldenseal preparations with optimal efficacy for the treatment or prevention of bacterial infections. More broadly, we also seek to explore one of the major guiding principles of complementary and alternative medicine, that the activity of multi-component therapies can be enhanced due to synergistic interactions. The methods validated as a part of this study are expected to prove useful to other investigators who must account for the synergistic interactions that play a role in the activity of many botanical medicines.