FabI Inhibitors as Potent, Gut Microbiome-Sparing Antibiotics

FabI 抑制剂是有效的、保护肠道微生物群的抗生素

• 批准号: 10673319
• 负责人: Paul Hergenrother
• 金额: $ 97.78万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-26 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673319
• 关键词: Acinetobacter baumannii; Acute; Acyl Carrier Protein; Amino Acids; Anti-Bacterial Agents; Antibiotics; Binding; Biological; Canis familiaris; Cell Culture Techniques; Clinic; Clinical; Clinical Trials; Collaborations; Collection; Critical Pathways; Data; Development; Docking; Dose; Drug Kinetics; Drug resistance; Enzymes; Escherichia coli; Escherichia coli drug resistance; Evaluation; FDA approved; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Industrialization; Infection; Investigational Therapies; Klebsiella pneumoniae; Knowledge; Laboratories; Lead; Ligands; Maximum Tolerated Dose; Modeling; Multi-Drug Resistance; Mus; Nature; Outcome; Oxidoreductase; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physicians; Pneumonia; Property; Proteins; Rattus; Resistance; Rodent; Roentgen Rays; Safety; Scientist; Sepsis; Soft Tissue Infections; Structure; Structure-Activity Relationship; Therapeutic Index; Time; Toxic effect; Toxicology; Translations; Vertebral column; Work; Writing; X-Ray Crystallography; bacterial resistance; clinical candidate; commensal bacteria; design; drug development; efficacy study; experience; experimental study; fighting; gut bacteria; gut dysbiosis; gut microbiome; in vivo; inhibitor; lead candidate; member; microbiome; microbiome research; novel; novel drug class; novel strategies; pathogen; pathogenic bacteria; preclinical study; resistance frequency; safety assessment; tool; trait

PROJECT SUMMARY/ABSTRACT The percent of Gram-negative bacterial infections that are resistant to common antibiotics has increased at an alarming rate over the last decade, and there is now an acute need for the discovery of novel antibiotics effective against multidrug-resistant Gram-negative pathogens. We have made progress understanding the relationship between physicochemical traits and compound accumulation in Gram-negative bacteria, enabling us to convert several antibiotics with Gram-positive-only activity into versions that possess activity against key Gram-negative pathogens. Most advanced is our FabI inhibitor fabimycin; FabI inhibition is a novel strategy with no approved antibiotics that hit this target. The nature of the FabI enzyme is that it is only essential in certain pathogenic bacteria, chief among them E. coli, K. pneumoniae, and A. baumannii; thus while fabimycin is effective against large clinical isolate panels of these pathogens, it has no activity against beneficial commensal bacteria that reside in the gut. A Gram-negative active antibiotic that spared the gut microbiome is without precedent and would be a very significant development, given the well-documented deleterious effects of broad-spectrum antibiotics in causing gut dysbiosis. In addition, our X-ray structures of fabimycin bound to FabI reveal critical interactions between the ligand and the protein backbone, making bacterial resistance much more challenging to arise than if interactions were solely with amino acid sidechains. Indeed, fabimycin has a low frequency of resistance, and resistance in cell culture only evolves over a long period of time. Excitingly, fabimycin is also active in multiple mouse and rat infection models, including those of soft tissue infection, pneumonia, sepsis, and UTI. To become a true clinical candidate the Therapeutic Index (TI) of fabimycin needs to be widened. Herein we propose development of more potent versions of fabimycin through application of a recent understanding of the relationship between compound efflux and structure that has emerged from our laboratories. Applying these lessons to fabimycin will enable us to systematically reduce its efflux liability, leading to MIC values for optimized derivatives that are 5-fold more potent than fabimycin and will thus have the appropriate TI for advancement. We have assembled a team of experts with the full suite of tools needed for this work: medicinal chemistry, understanding of efflux, access to large panels of clinical isolates, sophisticated models of antibacterial efficacy in mice and rats, and detailed pharmacokinetics and toxicology in mice, rats, and dogs, and microbiome studies in mice and dogs. Our Critical Path provides specific criteria for compound advancement and we are guided by best practices for antibiotic drug development as deliniated by the FDA. Our plan is to select the lead candidate by the end of Year 2, and then spend the remaining three years building a sophisticated data package that will facilitate rapid translation of this antibiotic to the clinic.

项目摘要/摘要 在 在过去的十年中，令人震惊的速度，现在有急需发现新型抗生素 有效防止耐多药的革兰氏阴性病原体。我们已经取得了了解 物理化学性状与革兰氏阴性细菌中化合物积累之间的关系，使得 美国将几种具有革兰氏阳性活性的抗生素转化为具有针对关键活动的活性的版本 革兰氏阴性病原体。最先进的是我们的Fabi抑制剂Fabimycin； Fabi抑制是一种新型策略 没有批准的抗生素击中该靶标。 Fabi酶的性质是，它仅在 某些致病性细菌，其中包括大肠杆菌，肺炎K.和A. baumannii；因此，fabimycin 对于这些病原体的大型临床分离株有效，它没有针对有益的活性 肠道中的共生细菌。避免肠道微生物组的革兰氏阴性活性抗生素是 鉴于有据可查的有害影响，没有先例，将是一个非常重要的发展 广谱抗生素引起肠道营养不良。此外，我们的fabimycin的X射线结构与 Fabi揭示了配体与蛋白质主链之间的关键相互作用，使细菌抗性极大 与仅与氨基酸SIDECHAINS相互作用相比，出现的挑战更大。确实，Fabimycin有一个 低频率的电阻和细胞培养中的耐药性仅在很长一段时间内演变。令人兴奋的是 Fabimycin在多种小鼠和大鼠感染模型中也有效，包括软组织感染的模型 肺炎，败血症和UTI。为了成为真正的临床候选者的治疗指数（TI） 要扩大。本文中，我们建议通过应用一种更有效版本的Fabimycin 最近对复合外排和结构之间的关系的了解 实验室。将这些课程应用于Fabimycin将使我们能够系统地减少其外排责任， 导致MIC值的优化衍生物比Fabimycin高5倍，因此将具有 适当的促进ti。我们已经组建了一个专家团队，并使用了所需的完整工具 对于这项工作：药物化学，对外排的理解，访问大量临床分离株， 小鼠和大鼠的抗菌功效的复杂模型，以及详细的药代动力学和毒理学 在小鼠和小鼠和狗的小鼠，大鼠，狗以及微生物组研究中。我们的关键道路提供了特定的标准 为了获得复合的进步，我们受到抗生素药物开发的最佳实践的指导 由FDA。我们的计划是在第二年底之前选择主要候选人，然后将剩余的三个 多年来建立了一个复杂的数据包，该包装将有助于将这种抗生素快速翻译为诊所。