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

基本信息

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
项目类别：
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

项目摘要

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."

全球多种耐药性（MDR）致病微生物的令人震惊的出现以及缺乏新型抗微生物的下一代投资组合威胁着人类和公共卫生。因此，它是全球优先考虑开发新型抗菌疗法以有效控制MDR细菌的优先事项。自然的和合成抗菌肽（AMP）作为治疗剂具有巨大的潜力，因为它们的独特通过膜渗透，快速杀死细菌的作用模式。但是，AMP的几个障碍开发限制其临床应用。该应用程序旨在克服当前的AMP限制，以开发针对MDR革兰氏阴性细菌感染的安全有效的广谱抗菌抗菌。我们的小说肽疗法A4AMP抗生素（A4X）是新一代的计算安排（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微不足道。我们研究的广泛结果表明，我们目前的领导候选人在500多个临床分离株中显示出对护理标准（SOC）抗生素的优质抗菌活性从医院和CDC＆FDA抗生素获得的难以杀死的MDR革兰氏阴性病原体电阻孤立银行。我们的A4X线索也比SOC的趋势要低得多抗生素。当静脉内给小鼠和大鼠施用时，A4X铅是安全且耐受性的，四个在小鼠血液循环中，最大耐受剂量的最大耐受剂量比colistin（最后一次度假抗生素）高。此外，我们已经证明了A4X铅对Klebsiella肺炎和细菌和呼吸道感染的小鼠模型中的鲍曼尼杆菌。在这个项目中，我们将携带消除临床前和预性非临床发展活动并执行结构活性关系（SAR）基于当前A4X的优化导致临床前发展并确定临床公用事业。我们将广泛研究这些新型的安全性，药代动力学/药效学和功效最有效A4X的小动物和大型动物中的抗菌剂。靶向细菌是MDR CDC紧急病原体威胁清单上的革兰氏阴性物种菌株，谁是最关键的全球优先1病原体清单（抗碳青霉菌的baumannii，克雷伯氏菌和肺炎大肠杆菌），包括抗colistin的抗性菌株。该提案针对紧迫的全球医疗需求新颖的抗生素并探讨了美国国家行动计划，用于打击抗生素耐药细菌及时的方式。这些研究的成功完成将对发展新颖的影响产生巨大影响一类抗生素能够与MDR作斗争的“超级细菌”。