THE DISCOVERY OF NOVEL ANTIBIOTICS THROUGH HIGH RESOLUTION STUDIES OF THE LARGE

通过大规模高分辨率研究发现新型抗生素

• 批准号: 8170611
• 负责人: Joseph Ippolito
• 金额: $ 0.54万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170611
• 关键词: Address; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Chemicals; Clinical; Collimator; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Funding; Goals; Gram-Positive Bacteria; Grant; Haloarcula marismortui; Infection; Institution; Medical; Pharmacologic Substance; Process; Property; Research; Research Personnel; Resistance; Resolution; Resources; Ribosomes; Source; Structure; Synchrotrons; United States National Institutes of Health; bacterial resistance; base; beamline; cell dimension; design; detector; drug discovery; inhibitor/antagonist; novel; rib bone structure; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rib-X Pharmaceuticals, Inc. is a small molecule drug discovery and development company whose goal is to address the medical difficulties presented by increasing bacterial resistance against current antibacterial agents by developing novel chemical classes of anti-infective molecules that target the ribosome. In order to shorten thedrug discovery process, we employ a structure-based design strategy that utilizes high resolution crystal structures of the 50S ribosome from the archaeal Haloarcula marismortui, complexed with small molecule inhibitors. Importantly, our research has already led to the identification of multiple clinical candidates with novel antibiotic properties for treating resistant infections. To augment our continuing drug discovery efforts, we have recently crystallized and determined the high resolution structure of the 50S ribosomal subunit from a Gram-positive bacterium. This allows us to target 50S regions not conserved between archeal and eubacterial kingdoms. Given the very large unit cell dimensions of our archeal and eubacterial 50S crystals, we are constrained to use not only a high intensity synchrotron source for x-rays, but also the best beamlines in terms of brightness, beam collimation and detector size, such as those found at NSLS.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Rib-X Pharmaceuticals，Inc.是一家小分子药物发现和开发公司，其目标是通过开发靶向核糖体的新型化学类抗感染分子来解决因增加细菌对当前抗菌剂的耐药性而带来的医疗困难。为了缩短药物发现过程，我们采用了基于结构的设计策略，该策略利用了来自古菌Haloarcula marismortui的50 S核糖体的高分辨率晶体结构，与小分子抑制剂复合。重要的是，我们的研究已经导致鉴定出具有治疗耐药性感染的新型抗生素特性的多种临床候选药物。为了加强我们持续的药物发现工作，我们最近结晶并确定了来自革兰氏阳性细菌的50 S核糖体亚基的高分辨率结构。这使我们能够靶向在古细菌和真细菌界之间不保守的50 S区域。由于我们的古细菌和真细菌50 S晶体的晶胞尺寸非常大，我们不仅要使用高强度的同步加速器X射线源，而且要使用亮度、光束准直和探测器尺寸方面的最佳光束线，例如在NSLS发现的那些。