Novel antimicrobials to combat Gram-negative bacteria

对抗革兰氏阴性菌的新型抗菌剂

• 批准号: 10888456
• 负责人: Daryl Murry
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10888456
• 关键词: Acinetobacter baumannii; Amphipathic Alpha Helix; Animal Model; Animals; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Biodistribution; Bioinformatics; Biological Assay; Cessation of life; Chemistry; Classification; Clinical; Colistin; Combined Modality Therapy; Communicable Diseases; Daptomycin; Data; Data Set; Databases; Development; Dose; Drug Kinetics; Drug resistance; Elements; Escherichia coli; Excretory function; Fostering; Foundations; Generations; Genes; Genetic study; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Gramicidin; Histology; Human; Immunology; In Vitro; Industrialization; Infection; Kidney; Klebsiella; Klebsiella pneumoniae; Knowledge; Laboratories; Lead; Life; Light; Liver; Lung; Lung infections; Medical center; Membrane; Metabolism; Methods; Microbial Biofilms; Microbiology; Modeling; Multi-Drug Resistance; Mus; Nebraska; Oryctolagus cuniculus; Pathogenesis; Pathology; Patients; Peptide Antibiotics; Peptides; Pharmacodynamics; Positioning Attribute; Property; Pseudomonas aeruginosa; Pseudomonas aeruginosa pneumonia; Regimen; Research; Resistance; Resistance development; Resources; Sepsis; Septicemia; Silver; Spleen; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Toxic effect; United States; Universities; absorption; analog; antimicrobial; antimicrobial peptide; bacterial resistance; cathelicidin; cathelicidin antimicrobial peptide; cecropin; colistin resistance; combat; design; doripenem; drug development; drug resistant pathogen; efficacy evaluation; efficacy study; experience; experimental study; humanized mouse; immunoregulation; improved; in silico; in vitro activity; in vivo; insight; meter; minimal inhibitory concentration; mouse model; novel; pathogen; pharmacokinetics and pharmacodynamics; response; structural biology; tool

Project Summary Drug-resistant Gram-negative pathogens such as Escherichia coli and Klebsiella pneumoniae are life- threatening and challenging to eliminate. It is stunning that they could avoid the killing of even colistin, the last resort antibiotic against these pathogens. While a comprehensive strategy is needed, the development of novel antimicrobials remains an important element. The objective of this project is to discover novel antimicrobials that can effectively eliminate drug-resistant Gram-negative pathogens that escape the killing of conventional antibiotics. Antimicrobial peptides are important candidates and some (e.g., daptomycin and gramicidin) are already in clinical use. However, it is not yet clear how to choose a promising template for antimicrobial developments. This project takes a new avenue to peptide discovery by combining our unique database tool with structural biology. The antimicrobial peptide database is an original resource established and maintained by the PI’s laboratory for over a decade. To facilitate our development, we have established universal peptide classification methods, set up criteria for peptide registration, developed the database filtering technology, and discovered a novel concept for peptide design. As exciting preliminary results, we have identified verine, which killed resistant bacteria, disrupted preformed biofilms in vitro and showed systemic efficacy in vivo against colistin-resistant Klebsiella comparable to doripenem. Remarkably, verine possesses a novel amphipathic structure, entirely different from the classic amphipathic helical structure. We hypothesize that verine is potent against antibiotic-resistant Gram-negative bacteria; structure-activity relationship, ADME (absorption, distribution, metabolism, excretion)-toxicity, pharmacokinetic/pharmacodynamics (PK/PD) studies and in vivo efficacy evaluation in different animal models will improve our knowledge and expand its therapeutic potential. To test our hypothesis, we have designed the following specific aims: (1) Elucidate the structure-activity relationship, test antimicrobial susceptibility of verine against Gram-negative pathogens in vitro alone or in combination with antibiotics and study the genetic basis of bacterial response; (2) Investigate the in vitro and in vivo toxicity and pharmacokinetic properties of verine and D-verine; and (3) Evaluate efficacy of verine against antibiotic-resistant Gram-negative pathogens in murine models. We are in an excellent position to pursue this project. Our preliminary results for each Aim support the feasibility of this project. To provide complementary expertise, the PI has assembled a strong team with expertise in bioinformatics, structural biology, peptide chemistry, antimicrobial assays, mechanism of action, microbiology, animal models, PK/PD, pathology, immunology, and industrial antimicrobial development. The completion of this project will foster new ideas to combat antimicrobial resistance, substantially improve our understanding of antimicrobial capability, PK/PD and in vivo efficacy of the novel peptide verine and its analog against various Gram-negative pathogens.

项目概要 耐药革兰氏阴性病原体，如大肠杆菌和肺炎克雷伯菌，是生命的威胁。 令人震惊的是，它们甚至可以避免杀死最后的粘菌素。 虽然需要采取综合策略来对抗这些病原体，但仍需要开发新的抗生素。 抗菌药物仍然是一个重要因素，该项目的目标是发现新型抗菌药物。 可以有效消除无法通过常规杀灭方法杀死的耐药革兰氏阴性病原体 抗菌肽是重要的候选物，其中一些（例如达托霉素和短杆菌肽）是。 然而，目前尚不清楚如何选择有前景的抗菌模板。 该项目通过结合我们独特的数据库工具，开辟了肽发现的新途径 抗菌肽数据库是建立和维护的原始资源。 为了促进我们的发展，我们建立了通用肽。 分类方法，制定肽注册标准，开发数据库过滤技术，以及 发现了肽设计的新概念 作为令人兴奋的初步结果，我们已经确定了 verine， 杀死耐药细菌，破坏体外预先形成的生物膜，并在体内显示出全身功效 值得注意的是，维林具有与多尼培南相当的抗粘菌素克雷伯氏菌的作用。 两亲结构，完全不同于经典的两亲螺旋结构。 维林对抗生素耐药的革兰氏阴性菌有效，结构活性关系，ADME； （吸收、分布、代谢、排泄）-毒性、药代动力学/药效学（PK/PD）研究 不同动物模型的体内功效评估将提高我们的知识并扩展其 为了检验我们的假设，我们设计了以下具体目标：（1）阐明 结构-活性关系，测试马对革兰氏阴性病原体的抗菌敏感性 (2) 单独或与抗生素联用进行体外研究，研究细菌反应的遗传基础； Verine 和 D-verine 的体外和体内毒性和药代动力学特性；以及 (3) 评估功效； 在小鼠模型中使用马来对抗抗生素耐药的革兰氏阴性病原体。 我们对每个目标的初步结果支持该项目的可行性。 提供互补的专业知识，PI组建了一支拥有生物信息学专业知识的强大团队， 结构生物学、肽化学、抗菌测定、作用机制、微生物学、动物模型、 该项目的完成将促进PK/PD、病理学、免疫学和工业抗菌药物的开发。 培育对抗抗菌药物耐药性的新思路，大幅提高我们对抗菌药物的了解 新型肽verine及其类似物对抗多种革兰氏阴性菌的能力、PK/PD和体内功效 病原体。