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."

全球范围内令人震惊的多药耐药（MDR）病原微生物的出现以及缺乏 下一代新型抗菌剂组合威胁人类和公共健康。因此，它是一个世界性的 优先考虑加快开发新的抗菌治疗方法，以有效控制MDR细菌。自然 合成抗菌肽（Amp）由于其独特的抗菌活性， 通过膜渗透快速杀灭细菌的作用方式。然而，AMP的几个障碍 发展限制了其临床应用。本申请旨在克服当前AMP的局限性， 安全有效的广谱抗菌药物，对抗MDR革兰阴性菌感染。我们的新型 肽治疗剂A4-AMP抗生素（A4 X）是新一代计算工程AMP （eAMP），其衍生自天然人宿主防御蛋白SPLUNC 1的抗微生物基序α-4，具有 对哺乳动物细胞的毒性可忽略不计。我们研究的广泛结果表明，我们目前的领先优势 在超过500种临床分离株中，候选药物显示出优于护理标准（SoC）抗生素的上级抗菌活性 从医院和CDC & FDA抗生素获得的难以杀灭的MDR革兰氏阴性病原体 电阻隔离库。我们的A4 X电极导线产生耐药性的趋势也比SoC低得多 抗生素A4 X电极导线在小鼠和大鼠静脉给药时安全且耐受性良好， 在小鼠血液循环中，最大耐受剂量比最后使用的抗生素粘菌素高10倍。 此外，我们已经证明了A4 X电极导线对肺炎克雷伯菌的有效性， 鲍曼不动杆菌在菌血症和呼吸道感染小鼠模型中的应用。在这个项目中，我们将 开展临床前和IND前非临床开发活动，并进行构效关系（SAR） 基于当前A4 X的优化，以推进临床前开发并确定临床 效用我们将广泛研究这些新药物的安全性、药代动力学/药效学和疗效。 A4 X抗菌剂在小型和大型动物中最有效。靶细菌是MDR 疾病预防控制中心紧急病原体威胁清单和世卫组织最关键的全球 优先1级病原体列表（碳青霉烯类耐药鲍曼不动杆菌、肺炎克雷伯菌和大肠埃希菌 大肠杆菌）和包括对粘菌素的抗性菌株。该提案针对的是全球未得到满足的迫切医疗需求， 新的抗生素，并解决了美国国家行动计划打击抗生素耐药细菌在一个 适时成功完成这些研究将对开发一部小说产生巨大的影响 这类抗生素能够对抗MDR“超级细菌。"