Developing a novel class of peptide antibiotics targeting carbapenem-resistant Gram-negative organisms

开发一类针对碳青霉烯类耐药革兰氏阴性生物的新型肽抗生素

• 批准号: 10674131
• 负责人: Yuanpu Peter Di
• 金额: $ 88.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674131
• 关键词: Acinetobacter baumannii; Address; Advanced Development; Amino Acids; Aminoglycosides; Animal Model; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacteremia; Bacteria; Biology; Blood Circulation; Ceftazidime; Cells; Cessation of life; Chemicals; Clinical; Clinical Trials; Colistin; Combating Antibiotic Resistant Bacteria; Data; Developing Countries; Development; Drug Kinetics; Engineering; Epithelial Cells; Erythrocytes; Escherichia coli; Evaluation; Exhibits; Fibroblasts; Fluoroquinolones; Future; Generations; Goals; Gram-Negative Bacterial Infections; Grant; Hospitals; Host Defense; Human; Incidence; Infection; Intellectual Property; International; Klebsiella pneumoniae; Lead; Legal patent; Leukocytes; Life; Lung; Lung infections; Mammalian Cell; Medical; Membrane; Modification; Molecular Conformation; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; Names; National Institute of Allergy and Infectious Disease; Non-Rodent Model; Organism; Pathogenicity; Peptide Antibiotics; Peptides; Pharmacodynamics; Pharmacology; Polymyxin B; Polymyxin Resistance; Polymyxins; Positioning Attribute; Preclinical Testing; Property; Proteins; Public Health; Rationalization; Rattus; Reporting; Research; Research Proposals; Resistance; Resistance development; Respiratory Tract Infections; Rodent Model; Safety; Series; Structure-Activity Relationship; Superbug; System; Therapeutic; Therapeutic Agents; Time; Toxic effect; Trademark; Treatment Cost; United States; Work; acute toxicity; antimicrobial; antimicrobial drug; antimicrobial peptide; bacterial resistance; beta-Lactamase; beta-Lactams; carbapenem resistance; clinical application; clinical development; commercialization; cytotoxicity; design; dosage; drug candidate; drug discovery; effective therapy; emerging pathogen; fighting; improved; inhibitor; intravenous administration; lead candidate; lead optimization; microorganism; mouse model; nephrotoxicity; next generation; novel; novel antibiotic class; novel therapeutics; pathogen; peptide drug; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; pre-clinical research; preclinical development; programs; public health relevance; rational design; resistant Klebsiella pneumoniae; resistant strain; standard of care; unnatural amino acids; virtual

The alarming emergence of multidrug-resistant (MDR) pathogenic microorganisms worldwide and the lack of next-generation portfolios of novel antimicrobials threaten human and public health. Therefore, it is a worldwide priority to expedite the development of novel antimicrobial therapies to control MDR bacteria effectively. Natural and synthetic antimicrobial peptides (AMPs) exhibit great potential as therapeutic agents because of their unique modes of action in fast-killing bacteria through membrane permeation. However, several barriers to AMP development limit its clinical application. This application aims to overcome current AMP limitations to develop a safe and effective broad-spectrum antimicrobial against MDR Gram-negative bacterial infection. Our novel peptide therapeutics A4-AMP antibiotics (A4X) is a new generation of computationally engineered AMPs (eAMPs) derived from the antimicrobial motif, alpha-4, of a natural human host defense protein SPLUNC1 with negligible toxicity to mammalian cells. The extensive results from our studies demonstrate that our current lead candidate displays superior antibacterial activity to standard of care (SoC) antibiotics in over 500 clinical isolates of difficult-to-kill MDR Gram-negative pathogens obtained from hospitals and the CDC & FDA Antibiotic Resistance Isolate Bank. Our A4X lead also has a much lower tendency to develop resistance than SoC antibiotics. The A4X lead is safe and well tolerated when intravenously administered to mice and rats, with a four times higher maximum tolerated dosage than colistin, a last resort antibiotic, in mouse blood circulation. Moreover, we have demonstrated the efficacy of the A4X lead against Klebsiella pneumoniae and Acinetobacter baumannii in mouse models of bacteremia and respiratory infection. In this project, we will carry out preclinical and pre-IND non-clinical development activities and perform structure-activity relationship (SAR) based optimization of the current A4X lead to advance the preclinical development and to determine the clinical utility. We will extensively examine the safety, pharmacokinetic/pharmacodynamic, and efficacy of these novel antimicrobial agents in small and large animals of the most effective A4X. The targeting bacteria are the MDR strains of Gram-negative species on the CDC's urgent pathogen threats list and WHO's the most critical global priority 1 pathogens list (carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumonia, and Escherichia coli) and, including resistant strains to colistin. This proposal targets the urgent unmet global medical need for novel antibiotics and addresses the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria in a timely manner. Successful completion of these studies will have an enormous impact on developing a novel class of antibiotics capable of fighting MDR "superbugs."

全球范围内多重耐药（MDR）病原微生物的惊人出现以及缺乏 下一代新型抗菌药物组合威胁人类和公共健康。因此，它是一个世界性的 当务之急是加快开发新型抗菌疗法，以有效控制耐多药细菌。自然的 和合成抗菌肽（AMP）因其独特的特性而展现出作为治疗剂的巨大潜力 通过膜渗透快速杀死细菌的作用方式。然而，AMP 存在一些障碍 的发展限制了其临床应用。该应用程序旨在克服当前的 AMP 限制来开发 安全有效的广谱抗菌药物，针对耐多药革兰氏阴性细菌感染。我们的小说 肽疗法 A4-AMP 抗生素 (A4X) 是新一代计算工程 AMP (eAMP) 源自天然人类宿主防御蛋白 SPLUNC1 的抗菌基序 alpha-4， 对哺乳动物细胞的毒性可以忽略不计。我们研究的广泛结果表明我们目前的领先地位 候选药物在 500 多种临床分离株中显示出优于标准护理 (SoC) 抗生素的抗菌活性 从医院以及 CDC 和 FDA 抗生素获得的难以杀死的 MDR 革兰氏阴性病原体 电阻隔离银行。我们的 A4X 引线产生阻力的趋势也比 SoC 低得多 抗生素。当静脉注射给小鼠和大鼠时，A4X 铅是安全的且耐受性良好，具有四个 小鼠血液循环中的最大耐受剂量比最后的抗生素粘菌素高出一倍。 此外，我们还证明了 A4X 引线对肺炎克雷伯菌和 菌血症和呼吸道感染小鼠模型中的鲍曼不动杆菌。在这个项目中，我们将携带 进行临床前和 IND 前非临床开发活动并执行结构-活性关系 (SAR) 基于当前 A4X 引线的优化，以推进临床前开发并确定临床 公用事业。我们将广泛检查这些新型药物的安全性、药代动力学/药效学和功效 抗菌药物对小型和大型动物最有效的是A4X。目标细菌是MDR 疾病预防控制中心的紧急病原体威胁清单和世卫组织的全球最严重的病原体威胁清单上的革兰氏阴性菌菌株 优先1级病原体列表（耐碳青霉烯类鲍曼不动杆菌、肺炎克雷伯菌和大肠杆菌） 大肠杆菌），包括对粘菌素具有抗性的菌株。该提案针对的是全球未满足的迫切医疗需求 新型抗生素并解决了美国抗击抗生素耐药性细菌国家行动计划 及时的方式。成功完成这些研究将对小说的开发产生巨大影响 一类能够对抗多重耐药“超级细菌”的抗生素。