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: 8363395
• 负责人: Joseph Ippolito
• 金额: $ 0.86万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363395
• 关键词: Address; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Chemicals; Clinical; Collimator; Complex; Crystallography; Funding; Goals; Gram-Positive Bacteria; Grant; Haloarcula marismortui; Infection; Light; Medical; National Center for Research Resources; Pharmacologic Substance; Principal Investigator; Process; Property; Research; Research Infrastructure; Resistance; Resolution; Resources; Ribosomes; Source; Structure; Synchrotrons; United States National Institutes of Health; bacterial resistance; base; beamline; cell dimension; cost; design; detector; drug development; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 the drug 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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 RIB-X制药公司是一家小分子药物发现和开发公司，其目标是通过开发针对核糖体的新型抗感染分子，解决细菌对现有抗菌剂的耐药性增加带来的医疗困难。为了缩短药物发现过程，我们采用了基于结构的设计策略，利用古生菌Haloarcula marismortui的50S核糖体的高分辨率晶体结构，并与小分子抑制剂复合。重要的是，我们的研究已经确定了多种临床候选药物，它们具有治疗耐药感染的新抗生素特性。为了加强我们持续的药物发现努力，我们最近结晶并确定了来自革兰氏阳性细菌的50S核糖体亚单位的高分辨率结构。这使我们能够瞄准在原始菌和真细菌王国之间不保守的50年代区域。考虑到我们的原生和真细菌50S晶体的单位尺寸非常大，我们不仅要使用高强度的同步加速器来进行X射线，还要使用亮度、光束准直和探测器尺寸方面最好的光束线，例如NSLS的那些光束线。