Antibacterial inhibitors of RnpA

项目摘要 针对新的细胞过程是维持新的抗生素开发管道的关键。在这方面， 我们推测，金黄色葡萄球菌的基本蛋白RnpA是一种独特的、可下药的抗菌剂。 目标。我们还预测，成功的RnpA抑制剂开发活动将提供新的广泛的 可用于金黄色葡萄球菌、其他革兰阳性菌治疗干预的广谱抗生素 生物体和革兰氏阴性病原体引起的直接和新的医疗保健问题。因此，我们有 组建了一个由微生物学家、生物化学家、化学家、计算和结构专家组成的多学科团队 生物学家将推出一种双管齐下的方法来确定生理上有希望的RnpA抑制剂是否可以 要合理地实现。具体地说，我们将使用全细胞RnpA抑制剂富集法和 一种有效的基于酶靶标的方法(Aim 1)和基于片段的筛选方法(Aim 2)以实现 RnpA抑制剂。该程序的一个好处是它允许将结构数据和计算数据集成在一起 合理的命中优化，无论他们的识别路线，并将指导我们最近解决的金黄色葡萄球菌 RNP一种X射线晶体结构。虽然使用的方法是尖端的，但这个项目的真正创新 可能驻留在目标本身。RnpA形成两种全酶，它们都介导不同的和推定的 独立必需的细胞功能、RNA降解和ptRNA成熟。因此，目标是 RnpA可能允许三种途径来识别具有治疗前景的化学类别的抑制剂和 项目的成功，包括那些抑制蛋白质的调制：1.mRNA衰退，2.ptRNA加工或 3.两个过程。

PROJECT ABSTRACT Targeting novel cellular processes is critical to maintaining a fresh antibiotic development pipeline. In that regard, we hypothesize that the essential Staphylococcus aureus protein, RnpA, is a unique and druggable antimicrobial target. We also predict that successful RnpA inhibitor development campaigns will provide new classes of broad spectrum antibiotics that can be used for the therapeutic intervention of S. aureus, other Gram-positive organisms and Gram-negative pathogens of immediate and emerging healthcare concern. Accordingly, we have assembled a multi-disciplinary team of microbiologists, biochemists, chemists, computational and structural biologists to launch a two-pronged approach to determine whether physiologically promising RnpA inhibitors can be reasonably achieved. Specifically, we will use a whole cell RnpA inhibitor enrichment assay combined with a validated enzyme target based approach (Aim 1) and fragment-based screening approach (Aim 2) to arrive at RnpA inhibitors. A benefit of this program is that it allows integration of structural and computational data for rational hit optimization regardless of their identification route and will be guided by our recently solved S. aureus RnpA X-ray crystal structure. While the approaches used are cutting-edge, the true innovation of this project may reside in the target itself. RnpA forms two holoenzymes, both of which mediate distinct and putatively independently essential cellular functions, RNA degradation and ptRNA maturation. Consequently, targeting RnpA potentially allows three routes of identifying therapeutically promising chemical classes of inhibitors and project success, including those that inhibit the protein's modulation of: 1. mRNA decay, 2. ptRNA processing or 3. Both processes.