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)感染是导致严重发病率的原因 以及全球范围内的死亡率。耐甲氧西林金黄色葡萄球菌感染特别可怕，因为它们很容易在 在医院环境和社区，他们通常不仅对β-内酰胺类药物耐药，而且对其他 主要的抗生素种类也是如此。临床上已经观察到对几种化合物的耐药性 最近推出用于治疗MRSA的药物。此外，有几个有充分记录的案件涉及混合 MRSA从VRE获得与万古霉素耐药相关的基因的感染。这是全哈佛的 由迈克尔·吉尔摩领导的抗生素耐药性计划项目成立，以促进合作 旨在解决MRSA中抗生素耐药性问题的研究。它将科学家和 在传染病相关领域、感染动物模型、细菌致病机制、细菌 生理学、抗药性的进化、新抗生素的发现和新抗生素的探索 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 探索对抗耐甲氧西林金黄色葡萄球菌的新化合物和策略。三种不同的方法，每种方法都涉及 将对不同的化合物类别和目标集进行调查。目标1将评估一个强大而有前途的 新型壁磷壁酸抑制剂作为抗MRSA药物。AIM II将解决以下潜在问题 磷壁酸D-丙氨酰化抑制剂作为抗MRSA药物。AIM III将提供测试版的全面列表 内酰胺类增强剂靶标在MRSA菌株中共享，并将探索一种新的策略来识别 以前发现的β-内酰胺增效剂的靶点，以使进一步的开发成为可能。

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.