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.

项目摘要 耐药的革兰氏阴性病原体，例如大肠杆菌和肺炎克雷伯氏菌 威胁和挑战以消除。他们可以避免杀死甚至是colistin，这是令人惊讶的 针对这些病原体的诉讼抗生素。虽然需要全面的策略，但新颖的发展 抗菌剂仍然是重要元素。该项目的目的是发现新颖的抗菌剂 这可以有效地消除抗药性的革兰氏阴性病原体，从而逃避杀害常规 抗生素。抗菌胡椒是重要的候选者，有些是（例如，daptomycin和gramicidin） 已经在临床上。但是，尚不清楚如何选择有希望的抗菌模板 发展。该项目通过组合我们独特的数据库工具，采用新的途径来发现胡椒。 结构生物学。抗菌肽数据库是建立和维护的原始资源 由PI的实验室工作了十多年。为了促进我们的发展，我们已经建立了通用肽 分类方法，设置肽注册的标准，开发了数据库过滤技术，并 发现了一个用于肽设计的新颖概念。作为令人兴奋的初步结果，我们已经确定了verine， 杀死了耐药细菌，体外预先形成的生物膜破坏并显示了体内的全身效率 反对抗co菌素的克雷伯氏菌，可与多甲基甲基相当。值得注意的是，Verine拥有一本小说 两亲性结构，与经典的两亲性螺旋结构完全不同。我们假设这一点 verine具有抗抗生素革兰氏阴性细菌的潜力。结构活动关系，add （吸收，分布，代谢，排泄） - 毒性，药代动力学/药效学（PK/PD）研究 并且在不同动物模型中的体内效率评估将改善我们的知识并扩大其知识 治疗潜力。为了检验我们的假设，我们设计了以下特定目的：（1）阐明 结构活性关系，对革兰氏阴性病原体的抗菌敏感性测试 单独或与抗生素结合并研究细菌反应的遗传基础； （2）调查 verine和d-verine的体外和体内毒性和药代动力学特性； （3）评估效率 在鼠模型中反对抗抗生素革兰氏阴性病原体的垂直剂。我们很棒 追求这个项目的位置。我们每个目标的初步结果都支持该项目的可行性。到 提供完整的专业知识，PI召集了一支拥有生物信息学专业知识的强大团队， 结构生物学，胡椒化学，抗菌测定，作用机理，微生物学，动物模型， PK/PD，病理学，免疫学和工业抗微生物发育。该项目的完成将 促进对抗抗菌素抗性的新想法，从而大大提高了我们对抗菌剂的理解 新型肽verine的能力，PK/PD和体内效率及其对各种革兰氏阴性的类似物 病原体。