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."

世界范围内令人震惊的多药耐药(MDR)病原微生物的出现和缺乏 下一代新型抗菌剂组合威胁着人类和公共健康。因此，它是一个世界性的 优先加快开发新的抗菌疗法，以有效控制耐多药细菌。天然 人工合成抗菌肽(AMPs)因其独特的性质而显示出巨大的治疗潜力 膜渗透快速杀灭细菌的作用方式。然而，AMP的几个障碍 发展限制了它的临床应用。此应用程序旨在克服当前AMP的限制，以开发 安全有效的广谱抗菌药治疗耐多药革兰氏阴性细菌感染。我们的小说 多肽治疗剂A4-AMP抗生素(A4X)是新一代计算机工程AMP (EAMPs)来自天然人类宿主防御蛋白SPLunc1的抗微生物基序α-4，具有 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，我们目前的领先优势 候选在500多个临床分离株中显示出比标准护理(SOC)抗生素更好的抗菌活性 医院获得性难治性耐多药革兰氏阴性菌与CDC、FDA抗生素 抵抗隔离银行。我们的A4X导线的阻力也比SoC低得多 抗生素。A4X铅静脉注射给小鼠和大鼠是安全和耐受性良好的，有4 在小鼠血液循环中，最大耐受量比最后一种抗生素粘菌素高出一倍。 此外，我们还展示了A4X铅对肺炎克雷伯菌和 鲍曼不动杆菌在小鼠菌血症和呼吸道感染模型中的作用。在这个项目中，我们将携带 开展临床前和IND前非临床开发活动，并执行结构-活性关系(SAR) 基于当前A4X的优化，以推进临床前开发并确定临床 实用程序。我们将广泛研究这些新型药物的安全性、药代动力学/药效学和有效性。 抗菌剂在小动物和大动物中效果最好的是A4X。靶标细菌是MDR 疾控中心紧急病原体威胁名单和世卫组织全球最危急名单上的革兰氏阴性菌菌株 优先病原菌清单(耐碳青霉烯类鲍曼不动杆菌、肺炎克雷伯氏菌和大肠杆菌 Coli)，包括对粘菌素具有耐药性的菌株。这项提案针对的是全球未得到满足的紧急医疗需求 新型抗生素和美国国家抗击抗生素耐药细菌行动计划 及时地。这些研究的成功完成将对小说的发展产生巨大的影响 一类能够对抗耐多药“超级细菌”的抗生素。