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.

项目摘要针对新的细胞过程对于维持新的抗生素开发渠道至关重要。在这方面，我们假设金黄色葡萄球菌的必需蛋白 RnpA 是一种独特且可药物化的抗菌剂目标。我们还预测，成功的 RnpA 抑制剂开发活动将提供新类别的广泛药物可用于金黄色葡萄球菌和其他革兰氏阳性菌的治疗干预的谱抗生素引起直接和新兴医疗保健关注的微生物和革兰氏阴性病原体。据此，我们有组建了一个由微生物学家、生物化学家、化学家、计算和结构学家组成的多学科团队生物学家将采取双管齐下的方法来确定生理上有前途的 RnpA 抑制剂是否可以得到合理的实现。具体来说，我们将使用全细胞 RnpA 抑制剂富集测定法并结合基于经过验证的酶靶标的方法（目标 1）和基于片段的筛选方法（目标 2），以得出 RnpA 抑制剂。该程序的一个好处是它允许集成结构和计算数据无论其识别途径如何，合理的命中优化都将以我们最近解决的金黄色葡萄球菌为指导 RnpA X射线晶体结构。虽然所使用的方法是前沿的，但该项目的真正创新可能驻留在目标本身。 RnpA 形成两种全酶，两者均介导不同且推定的独立的重要细胞功能、RNA 降解和 ptRNA 成熟。因此，针对 RnpA 可能允许通过三种途径来识别有治疗前景的化学类型的抑制剂和项目成功，包括抑制蛋白质调节的项目：1. mRNA 衰减，2. ptRNA 加工或 3. 两个过程。