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.

项目概要/摘要 对常见抗生素具有耐药性的革兰氏阴性细菌感染的百分比以惊人的速度增加 过去十年以惊人的速度发展，现在迫切需要发现新型抗生素 对多重耐药革兰氏阴性病原体有效。我们在理解上取得了进展 革兰氏阴性细菌的理化特性与化合物积累之间的关系，使得 我们将几种仅具有革兰氏阳性活性的抗生素转化为具有针对关键活性的活性的版本 革兰氏阴性病原体。最先进的是我们的FabI抑制剂法比霉素； FabI 抑制是一种新策略 没有批准的抗生素可以达到这个目标。 FabI 酶的性质是它仅在 某些致病菌，主要是大肠杆菌、肺炎克雷伯菌和鲍曼不动杆菌；因此，法比霉素 对这些病原体的大量临床分离组有效，但对有益的无活性 存在于肠道中的共生细菌。一种不受肠道微生物群影响的革兰氏阴性活性抗生素是 史无前例，鉴于其有害影响已得到充分记录，这将是一个非常重大的进展 广谱抗生素引起肠道菌群失调。此外，我们的法比霉素的 X 射线结构结合 FabI揭示了配体和蛋白质主链之间的关键相互作用，使细菌耐药性大大提高 比仅与氨基酸侧链相互作用更具挑战性。事实上，法比霉素具有 耐药性发生率低，并且细胞培养中的耐药性仅在很长一段时间内才会进化。令人兴奋的是， 法比霉素在多种小鼠和大鼠感染模型中也具有活性，包括软组织感染模型， 肺炎、败血症和尿路感染。要成为真正的临床候选人，法比霉素需要治疗指数 (TI) 被拓宽。在此，我们建议通过应用开发更有效的法比霉素版本 最近对化合物流出与结构之间关系的理解是从我们的研究中得出的 实验室。将这些经验教训应用于法比霉素将使我们能够系统地减少其外排责任， 导致优化衍生物的 MIC 值比法比霉素强 5 倍，因此具有 适合晋升的 TI。我们组建了一支专家团队，拥有所需的全套工具 对于这项工作：药物化学、对外排的了解、获得大量临床分离株、 小鼠和大鼠抗菌功效的复杂模型，以及详细的药代动力学和毒理学 小鼠、大鼠和狗的微生物组研究。我们的关键路径提供了具体的标准 对于化合物的进步，我们以抗生素药物开发的最佳实践为指导 由 FDA 批准。我们的计划是在第二年年底选出主要候选人，然后用剩下的三个 多年来构建了一个复杂的数据包，将有助于这种抗生素快速转化为临床。