权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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."

多药耐药（MDR）病原微生物在世界范围内的惊人出现和缺乏