Antibacterial inhibitors of RnpA

RnpA 抗菌抑制剂

基本信息

批准号：
9913451
负责人：
Paul Dunman
金额：
$ 70.47万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-07 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913451
关键词：
AIDS/HIV problem Affect Alanine Americas Amino Acids Animal Model Anti-Bacterial Agents Antibiotics Bacterial Infections Bacterial RNA Biological Biological Assay Biophysics Catalytic RNA Cause of Death Cell physiology Cells Chemicals Communicable Diseases Coupled Crystallization Data Decision Making Development Disease ESKAPE pathogens Engineering Enzymes Exhibits Genus staphylococcus Goals Healthcare Holoenzymes Human In Vitro Incidence Infection Laboratories Lead Libraries Ligands Mediating Messenger RNA Multiple Bacterial Drug Resistance Mutagenesis Mutation Organism Pharmacologic Substance Physicians Physiological Process Protein Biosynthesis Proteins RNA RNA Degradation RNA chemical synthesis RNase P Roentgen Rays Route Sampling Scanning Severities Societies Staphylococcus aureus Structural Biologist Structure Testing Therapeutic Therapeutic Intervention Therapeutic Uses analog antimicrobial bacterial resistance base cellular targeting design drug development drug discovery high throughput screening improved inhibitor/antagonist innovation lead optimization mRNA Decay mRNA Transcript Degradation member mouse model multidisciplinary novel pathogen pathogenic bacteria programs screening screening program small molecule small molecule inhibitor structural biology success tRNA Precursor

项目摘要

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.

项目摘要靶向新的细胞过程对于维持新的抗生素发育管道至关重要。在这方面，我们假设必需的金黄色葡萄球菌蛋白RNPA是一种独特而可药的抗菌剂目标。我们还预测，成功的RNPA抑制剂开发活动将为广泛的新类别提供光谱抗生素可用于金黄色葡萄球菌的治疗干预，其他革兰氏阳性直接和新兴医疗保健的生物和革兰氏阴性病原体。因此，我们有组建了一个微生物学家，生物化学家，化学家，计算和结构的多学科团队生物学家推出一种两国的方法，以确定生理上有希望的RNPA抑制剂是否可以合理实现。具体而言，我们将使用全细胞RNPA抑制剂富集分析结合经过验证的基于酶的方法（目标1）和基于碎片的筛选方法（AIM 2）到达 RNPA抑制剂。该程序的一个好处是，它允许整合结构和计算数据无论其识别途径如何 RNPA X射线晶体结构。在使用的方法是尖端的，但该项目的真正创新可能位于目标本身中。 RNPA形成两个全酶，两者都介导了不同独立的必需细胞功能，RNA降解和PTRNA成熟。因此，定位 RNPA可能允许三种识别治疗疗法的抑制剂的化学类别和项目成功，包括抑制蛋白质调节的项目：1。mRNA衰变，2。ptRNA加工或 3。这两个过程。