Development of an antimicrobial peptide therapeutic for Pseudomonas infections

开发治疗假单胞菌感染的抗菌肽

• 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
• 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

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)： 这项应用将集中在将一种新的抗菌肽推向临床试验所需的关键临床前实验上。我们根据天然宿主防御分子CAP37的天然序列，成功地合成了一个含有25个氨基酸的生物活性多肽(CAP3720-44)。CAP372O-44及其类似物CAP372O-44Ser26和CAP372O-44Ser42对铜绿假单胞菌和鲍曼不动杆菌等革兰氏阴性菌具有较强的抗菌活性。CAP37肽对抗生素活性的另一个重要作用是它们结合和中和内毒素或内毒素的毒性效应的能力，内毒素是革兰氏阴性生物外膜的一种成分。我们假设CAP37多肽是一类新的抗生素，由于它们具有新的抗菌活性和内毒素结合活性，将被证明是治疗耐药医疗保健相关感染的有效药物。我们的目标是开发一种新的抗生素，用于在急性医院环境下治疗严重的革兰氏阴性感染。我们最初的适应症是治疗铜绿假单胞菌引起的菌血症和医院内肺炎。此申请旨在满足成功向FDA提交研究用新药申请所需的关键里程碑。该应用有五个主要的研究和开发领域，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)建立体内疗效的高级疾病模拟研究，以及5)药代动力学、毒理学和安全药理学。目的1：建立CAP37肽合成的放大程序，以确保有足够的GMP类化合物用于实验分析，并确定用于临床试验的每克成本的可行性。目的：采用临床和实验室标准研究所(CLSI)参考方法测定CAP37多肽的体外活性和抗菌谱，并检测生物通过自发突变和顺序突变对CAP37多肽产生耐药性的倾向。目的：研究CAP37多肽对啮齿动物和非人灵长类动物肺炎和菌血症模型的体内疗效。目的4：确定多肽在两个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。这一应用将为一种治疗多种严重革兰氏阴性感染的新型抗生素的作用机制提供关键的见解。与公共卫生的相关性。迫切需要新的抗生素来治疗与卫生保健相关的感染。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上升，这是一个严重的公共卫生问题。寻找具有强大抗菌活性和低耐药性倾向的新疗法将对公共卫生具有重要意义。