Development of an antimicrobial peptide therapeutic for Pseudomonas infections

开发治疗假单胞菌感染的抗菌肽

基本信息

批准号：
8142110
负责人：
Heloise. ANNE Pereira
金额：
$ 71.05万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8142110
关键词：
Acinetobacter Acinetobacter baumannii Acute Aerobic Amino Acids Animals Anti-Bacterial Agents Anti-Infective Agents Antibiotic Therapy Antibiotics Antigen-Presenting Cells Antimicrobial Cationic Peptides Area Attenuated Bacteremia Bacteria Binding Biological Biological Assay Blood Vessels Cardiovascular system Cell physiology Cells Characteristics Clinical Clinical Trials Coagulation Process Communicable Diseases Complex Conscious Cysteine Data Development Disease model Disulfides Dose Drug Formulations Drug Kinetics Drug resistance Endothelial Cells Endotoxic Shock Endotoxins Ensure Epithelial Cells Escherichia coli Goals Gram-Negative Bacteria Healthcare Heart Diseases Hospitals Host Defense Human Immune system In Vitro Incidence Infection Inflammatory Institutes Intention Intravenous Investigation Investigational Drugs Investigational New Drug Application Laboratories Lead Lipopolysaccharides Lung Malignant Neoplasms Mammalian Cell Membrane Methods Microbiology Microglia Minimum Inhibitory Concentration measurement Modeling Monkeys Mononuclear Morbidity - disease rate Mus Mutation New Zealand Nosocomial pneumonia Organism Oryctolagus cuniculus Oxygen Papio Pathology Patients Peptide Antibiotics Peptides Persons Pharmacology Pharmacology and Toxicology Plasma Plasma Proteins Pneumonia Positioning Attribute Primates Procedures Production Protein Binding Protein Isoforms Proteins Pseudomonas Pseudomonas Infections Pseudomonas aeruginosa Public Health Rattus Recovery Research Research Personnel Resistance Resistance development Risk Rodent Rodent Model Safety Salmonella typhimurium Screening procedure Serine Smooth Muscle Myocytes Structure Survival Rate System Testing Therapeutic Time Toxic effect Toxicology advanced disease analog antimicrobial antimicrobial drug antimicrobial peptide bactericide base corneal epithelium cost effective therapy experimental analysis in vivo inflammatory marker insight killings liquid chromatography mass spectrometry meetings monocyte mortality mouse model neutrophil nonhuman primate novel novel therapeutics pathogen peptide analog pre-clinical preclinical study programs research study respiratory response scale up synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): This application will focus on the critical pre-clinical experiments required to advance a novel antibiotic peptide into clinical trials. We successfully synthesized a twenty-five amino acid bioactive peptide (CAP372o-44) based on the native sequence of the natural host defense molecule known as CAP37. CAP372o-44 and two peptide analogs, CAP372o-44Ser26 and CAP372o-44 Ser42, have potent antimicrobial activity for Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii. Of additional importance to the antibiotic activity of CAP37 peptides, is their ability to bind and neutralize the toxic effects of lipopolysaccharide (LPS) or endotoxin, a component of the outer membrane of Gram-negative organisms. We hypothesize that CAP37 peptides are a new class of antibiotic, and due to their novel mode of antimicrobial activity and LPS binding activity, will prove to be effective therapies for drug-resistant healthcare-associated infections. Our goal is the development of a novel antibiotic for the treatment of severe Gram-negative infections in an acute hospital setting. Our initial indications are for the treatment of bacteremia and nosocomial pneumonia due to P. aeruginosa. This application is structured to satisfy the key milestones required for successful submission of an investigational new drug application to the FDA. The application has five major areas of study and development which include 1) selection of lead compound, 2) production and formulation, 3) in vitro microbiology, 4) advanced disease modeling studies to establish in vivo efficacy, and 5) pharmacokinetics, toxicology, and safety pharmacology. Aim 1: To establish the scale-up procedure of the synthesis of CAP37 peptides to ensure sufficient GMP-like compound for experimental analysis and to determine feasibility of cost per gram at scale for use in clinical trials. Aim 2: To determine the in vitro efficacy and antimicrobial spectrum of activity of the CAP37 peptides using Clinical and Laboratory Standards Institute (CLSI) reference methods and to examine the propensity for organisms to develop resistance to CAP37 peptides via spontaneous and sequential mutation. Aim 3: To determine the in vivo efficacy of CAP37 peptides in rodent and nonhuman primate models of Pseudomonas pneumonia and bacteremia. Aim 4: To determine the pharmacokinetics of the peptides in two animal species and to perform the required safety pharmacology and toxicology to meet FDA requirements for an IND submission. This application will provide key insights into the mechanism of action of a novel antibiotic for treating multiple severe Gram-negative infections. Relevance to public health. There is a critical need for new antibiotics to treat health-care associated infections. The increased incidence of pathogen resistance to current antibiotics results in dramatically increased morbidity and mortality rates, a serious public health issue. Identifying new therapeutics with strong antimicrobial activity and low propensity to induce resistance will be of great public health importance.

描述（由申请人提供）：该申请将重点关注将新型抗生素肽推进临床试验所需的关键临床前实验。我们基于天然宿主防御分子 CAP37 的天然序列，成功合成了 25 个氨基酸的生物活性肽 (CAP372o-44)。 CAP372o-44 和两种肽类似物 CAP372o-44Ser26 和 CAP372o-44 Ser42 对革兰氏阴性菌（包括铜绿假单胞菌和鲍曼不动杆菌）具有有效的抗菌活性。对于 CAP37 肽的抗生素活性来说，更重要的是它们能够结合和中和脂多糖 (LPS) 或内毒素（革兰氏阴性生物体外膜的成分）的毒性作用。我们假设 CAP37 肽是一类新型抗生素，由于其新颖的抗菌活性和 LPS 结合活性，将被证明是治疗耐药性医疗相关感染的有效疗法。我们的目标是开发一种新型抗生素，用于治疗急性医院环境中的严重革兰氏阴性菌感染。我们的初步适应症是治疗铜绿假单胞菌引起的菌血症和院内肺炎。该申请的结构是为了满足向 FDA 成功提交新药研究申请所需的关键里程碑。该应用程序有五个主要研究和开发领域，包括 1) 先导化合物的选择，2) 生产和配方，3) 体外微生物学，4) 建立体内功效的高级疾病模型研究，以及 5) 药代动力学、毒理学、和安全药理学。目标 1：建立 CAP37 肽合成的放大程序，以确保有足够的类 GMP 化合物用于实验分析，并确定大规模用于临床试验的每克成本的可行性。目标 2：使用临床和实验室标准研究所 (CLSI) 参考方法确定 CAP37 肽的体外功效和抗菌活性谱，并检查生物体通过自发和连续突变对 CAP37 肽产生耐药性的倾向。目标 3：确定 CAP37 肽在啮齿动物和非人灵长类动物假单胞菌肺炎和菌血症模型中的体内功效。目标 4：确定肽在两种动物物种中的药代动力学，并执行所需的安全药理学和毒理学以满足 FDA 对 IND 提交的要求。该应用将为治疗多种严重革兰氏阴性菌感染的新型抗生素的作用机制提供重要见解。与公共卫生的相关性。迫切需要新的抗生素来治疗医疗相关感染。病原体对当前抗生素耐药性的增加导致发病率和死亡率急剧增加，这是一个严重的公共卫生问题。确定具有强抗菌活性和低诱导耐药性的新疗法对于公共卫生具有重要意义。