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Novel antimicrobial agents to overcome antibiotic resistant Pseudomonas and MRSA respiratory infection

新型抗菌药物可克服抗生素耐药性假单胞菌和 MRSA 呼吸道感染

基本信息

批准号：
10204921
负责人：
Yuanpu Peter Di
金额：
$ 52.47万
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：
2017
资助国家：
美国
起止时间：
2017-07-12 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204921
关键词：
Address Affect Amino Acids Antibiotic Resistance Antibiotics Antimicrobial Cationic Peptides Bacteremia Bacteria Bacterial Antibiotic Resistance Bacterial Infections Biological Assay Biophysics Centers for Disease Control and Prevention (U.S.)Cessation of life Child Chlamydia trachomatis Circular Dichroism Clinical Clinical Trials Colistin Communicable Diseases Cystic Fibrosis Data Development Drug Industry Drug Kinetics Drug resistance ESKAPE pathogens Effectiveness Elderly Engineering Environment Epithelial Cells Exhibits Foundations Frequencies Health Care Costs Hospitalization Human Illness Days Immune In Vitro Incidence Individual Injections Intravenous Knowledge Lead Length Life Link Lung Lung diseases Mediating Medical Membrane Methods Modeling Molecular Monkeys Multi-Drug Resistance Multiple Bacterial Drug Resistance Mus Pathogenicity Patients Peptides Pharmacologic Substance Phenotype Population Predisposition Productivity Property Pseudomonas Pseudomonas aeruginosa Public Health Pulmonary Fibrosis Quality of life Recurrence Research Resistance Resistance development Resort Respiratory Tract Infections Rifampin Roentgen Rays Safety Sepsis Series Sodium Chloride Staphylococcus aureus infection Stress Structure Testing Therapeutic Therapeutic Agents Therapeutic Index Time Toxic effect Treatment Protocols United States airway epithelium antibiotic resistant infections antimicrobial antimicrobial drug antimicrobial peptide arginylvaline bacterial resistance bactericide base cathelicidin antimicrobial peptide clinically relevant combat comparative cost cystic fibrosis patients cytotoxic drug resistant bacteria drug resistant pathogen economic impact effective therapy efficacy testing emerging pathogen extensive drug resistance genome sequencing human disease in vitro activity in vivo indexing iterative design lead candidate methicillin resistant Staphylococcus aureus microorganism mortality mouse model natural antimicrobial novel novel therapeutics optimal treatments pathogen peptide structure pneumonia treatment preclinical study protein aminoacid sequence public health relevance resistance frequency respiratory vaginal microbicide whole genome

项目摘要

According to the Centers for Disease Control and Prevention, antibiotic-resistant infections are already linked to 23,000 deaths and 2 million illnesses in the United States each year. Many of the mortality cases are associated with life-threatening complications, especially sepsis. Estimates of the economic impact vary, but have ranged as high as $20 billion in excess direct healthcare costs, and as much as $35 billion in lost productivity from hospitalizations and sick days. Unfortunately, the problem is worsening because of an alarming increase in antibiotic-resistant bacteria in recent years and the void in the development and discovery of new antibiotics by pharmaceutical companies over the last three decades. As a consequence, development of novel therapies to effectively combat drug-resistant bacteria is not only of scientific and medical importance, but a national priority. We have developed a series of rationally engineered cationic antimicrobial peptides (eCAPs) using different amino acids computationally arranged to achieve in vitro inactivation of diverse drug- resistant bacterial strains. One of the lead compounds, WLBU2 (made only of Arg, Val, and Trp), has demonstrated potent bactericidal activity against diverse difficult-to-treat drug resistant pathogens that have developed resistance to other membrane-active compounds, such as the natural antimicrobial peptide (AMP) LL37 and colistin, an antibiotic of last resort. In addition, we have demonstrated a substantially lower tendency for bacteria to develop resistance to WLBU2 compared to standard antibiotic agents and natural AMPs. Importantly, WLBU2 demonstrates in vivo efficacy in a murine model of P. aeruginosa sepsis when the bacteria were systemically administered. Because of an initially narrow therapeutic index (TI ≤ 5), we are continuously optimizing eCAP structure using a systematic iterative design approach to lower host toxicity and enhance potency and stability. Preliminary data indicate that some of these Trp-based eCAPs (collectively referred to as W2eCAPs) have already demonstrated a higher TI. Based on the exciting results from these exploratory studies, the use of W2eCAPs to overcome bacterial resistance is an appealing concept. Hence, we hypothesize that W2eCAPs will display enhanced bactericidal activities against DR bacteria as well as negligible host toxicity and, therefore, can be used as an effective therapy to treat pneumonia-induced sepsis. Due to the unique lung microenvironment, many questions remain to be answered before the clinical ideal of using W2eCAPs can be realized. Thus, the primary purpose of this proposal is to understand: 1) how W2eCAPs exert their antimicrobial activities against major respiratory drug resistant pathogens in conditions associated with the lung microenvironment; 2) the molecular mechanisms used by W2eCAPs to kill bacteria; (3) the optimal treatment regimens (systemic compared to airway delivery) to select the W2eCAP with the highest TI; and (4) the pharmacokinetic properties of the selected W2eCAPs.

根据美国疾病控制与预防中心（Centers for Disease Control and Prevention）的数据，抗生素耐药性感染已经存在关联

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Analysis of RNA Sequencing Data Using CLC Genomics Workbench.

DOI：
10.1007/978-1-0716-0223-2_4
发表时间：
2020-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Liu, Chia-Hsin;Di, Y Peter
通讯作者：
Di, Y Peter

Heterogeneous-Backbone Proteomimetic Analogues of Lasiocepsin, a Disulfide-Rich Antimicrobial Peptide with a Compact Tertiary Fold.

DOI：
10.1021/acschembio.2c00138
发表时间：
2022-04-15
期刊：
ACS CHEMICAL BIOLOGY
影响因子：
4
作者：
Cabalteja, Chino C.;Lin, Qiao;Harmon, Thomas W.;Rao, Shilpa R.;Di, Y. Peter;Horne, W. Seth
通讯作者：
Horne, W. Seth

Phloretin, an Apple Polyphenol, Inhibits Pathogen-Induced Mucin Overproduction.