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）：