Subproject 1 Compounds and Strategies for Treating MRSA and VRE

摘要 侵袭性耐甲氧西林金黄色葡萄球菌（MRSA）感染是导致显著发病率的原因 和死亡率。MRSA感染是特别可怕的，因为它们很容易传播， 在医院环境和社区中，他们通常不仅对β内酰胺类抗生素耐药，而且对其他抗生素耐药。 抗生素的主要种类也是如此。已经观察到对几种化合物的临床耐药性 最近被用于治疗MRSA。此外，有几个证据充分的案件涉及混合 MRSA从VRE获得赋予万古霉素抗性的基因的感染。这个哈佛范围的 由Michael Gilmore领导的抗生素耐药性项目旨在促进合作， 该研究旨在解决MRSA的抗生素耐药性问题。它将科学家们聚集在一起， 传染病、感染动物模型、细菌致病机理、细菌学、 生理学，耐药性的进化，新型抗生素的发现，以及新的抗生素的探索。 克服抗生素耐药性感染的方法。这个子项目的重点是发现和 探索对抗MRSA的新化合物和策略。三种不同的方法，每种方法都涉及 不同的化合物类别和目标集，将被调查。目标1将评估一个有效的和有前途的 作为抗MRSA药剂的新结构类别的壁磷壁酸抑制剂。目标二将探讨 作为抗MRSA剂的磷壁酸D-丙氨酰化抑制剂。目标III将提供一个全面的测试列表 内酰胺增效剂的目标是MRSA菌株之间共享，并将探索一种新的策略，以确定 以前发现的β-内酰胺增效剂的目标，使进一步的发展。

ABSTRACT Invasive methicillin resistant Staphylococcus aureus (MRSA) infections are responsible for significant morbidity and mortality worldwide. MRSA infections are particularly frightening since they are readily transmitted both in hospital settings and in the community, and they are typically resistant not only to beta lactams, but to other major classes of antibiotics as well. Clinical resistance has already been observed to several compounds introduced recently to treat MRSA. Moreover, there have been several well-documented cases involving mixed infections in which MRSA acquired genes conferring vancomycin resistance from VRE. This Harvard-wide Program Project on antibiotic resistance, led by Michael Gilmore, was established to foster collaborative research aimed at addressing the problem of antibiotic resistance in MRSA. It brings together scientists with expertise in relevant areas of infectious disease, animal models of infection, bacterial pathogenesis, bacterial physiology, the evolution of resistance, the discovery of novel antibiotics, and the exploration of new approaches to overcome antibiotic resistant infections. This subproject is focused on the discovery and exploration of novel compounds and strategies to combat MRSA. Three different approaches, each involving different compound classes and sets of targets, will be investigated. Aim 1 will evaluate a potent and promising new structural class of wall teichoic acid inhibitors as anti-MRSA agents. Aim II will address the potential of inhibitors of teichoic acid D-alanylation as anti-MRSA agents. Aim III will provide a comprehensive list of beta lactam potentiator targets that are shared among MRSA strains, and will explore a new strategy to identify targets of previously discovered beta lactam potentiators to enable further development.