Host Directed Orynotide for MDR Gram Negative Bacterial Infections

宿主定向 Orynotide 用于治疗耐多药革兰氏阴性细菌感染

• 批准号: 10674221
• 负责人: Justin Blaine Schaal
• 金额: $ 100.6万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-21 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674221
• 关键词: ADME Study; Acinetobacter baumannii; Address; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Antibodies; Applications Grants; Bacteremia; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Model; Biochemical Pathway; Biological; Biology; Blood; Canis familiaris; Carbapenems; Cell Communication; Cells; Cercopithecidae; Cessation of life; Chemistry; Combined Modality Therapy; Communicable Diseases; Consensus; Cyclization; Data; Defensins; Development; Disease Outbreaks; Dose; Drug Kinetics; E. coli bacteremia; Engineering; Escherichia coli; Evaluation; Flow Cytometry; Goals; Gram-Negative Bacterial Infections; Hand; Health; Host Defense; Human; Immune; Immune response; Immunotherapeutic agent; In Vitro; Infection; Inflammation; Inflammatory; Intraperitoneal Injections; Investments; Klebsiella pneumoniae; Lead; Leukocytes; Libraries; Malignant Neoplasms; Mass Spectrum Analysis; Maximum Tolerated Dose; Mediating; Methods; Modeling; Molecular; Molecular Target; Multi-Drug Resistance; Multidrug-resistant Acinetobacter; Multiple Bacterial Drug Resistance; Mus; Neutrophil Infiltration; Neutrophilia; Nosocomial Infections; Peptide Hydrolases; Peptides; Peritoneal; Peritoneal Sepsis; Peritoneal lavage; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology Study; Plasma; Preventive; Production; Property; Protein Isoforms; Proteins; Protocols documentation; Public Health; Publishing; Radiolabeled; Rattus; Reagent; Research; Resistance; Risk; Route; Safety; Sepsis; Septic Shock; Septicemia; Signal Pathway; Spleen; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; United States; Vertebral column; Whole Blood; antibody test; antimicrobial; antimicrobial drug; bacterial resistance; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; colistin resistance; combat; cytokine; design; drug candidate; fungus; immunogenicity; improved; in vivo; intraperitoneal; microbial; microorganism; mouse model; novel; novel therapeutics; pathogen; pathogenic bacteria; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; preclinical development; recruit; response; response biomarker; safety study; theta-defensin; uptake

PROJECT SUMMARY The goal of this grant proposal is to advance the preclinical development of a novel macrocyclic peptide, Orynotide™ MTD12813, for treatment of multidrug resistant (MDR) Gram negative bacterial infections, with the initial focus being on infections caused by carbapenem-resistant Enterobacteriaceae (CRE). The emergence of infections by multiple CRE pathogens has created an urgent public health threat, because carbapenems are drugs of last resort for infections caused by an increasing fraction of MDR bacterial pathogens. Just two species, Klebsiella pneumoniae and Escherichia coli, cause an estimated 140,000 nosocomial infections per year in the United States alone, and many are carbapenem resistant. There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. The applicants, leaders in the field of θ-defensin biology, are responding to this need by developing Orynotides, a new class of host-directed antimicrobial macrocyclic peptides bioinspired by the structural and biological properties of theta (θ)-defensins, macrocyclic peptides expressed exclusively in Old World monkeys (but not humans). Exploiting the pleiotropic host defense properties of θ-defensins, we produced a library of novel Orynotides that includes several compounds that are highly effective in MDR Gram negative septicemia models. Hit-to-lead studies identified MTD12813 as the lead Orynotide candidate for preclinical development as a first- in-class immunotherapeutic agent for MDR Gram negative infections. In the mouse peritoneal sepsis model, single dose administration of MTD12813 is highly effective (enhanced survival with concomitant bacterial clearance) against multiple strains of CRE-K. pneumoniae and CRE-E. coli, and additionally was shown to be effective in septicemia caused by MDR Acinetobacter baumannii. Consistent with the range of pathogens against which MTD12813 is active in vivo, we showed that the peptide’s mode of action is immunotherapeutic, promoting host-mediated bacterial clearance, stimulating phagocytosis and neutrophil recruitment, while modulating levels of otherwise dysregulated proinflammatory cytokines. These data indicate that MTD12813 is a novel immunotherapeutic agent effective in the treatment of Gram negative bacterial pathogens. The peptide is readily manufacturable ( ~1.5 g on hand), highly stable in human plasma and whole blood, resistant to bacterial proteases, and well tolerated when administered by numerous routes. In the proposed studies, we will advance the preclinical characterization of MTD12813. Aim 1 studies will include production of GLP MTD12813 and other critical reagents, pharmacokinetic (PK) and PK/pharmacodynamic analyses, and ADME studies. Aim 2 will focus on illuminating mechanism(s) of action at the cellular and molecular level. Aim 3 objectives will include preclinical non-GLP safety and toxicokinetic studies in rats and beagle dogs, evaluation of immunogenicity, development of an antidrug antibody assay, and culminate with formal GLP safety studies. The goal of these aims is to advance the preclinical development of MTD12813 to IND filing with the FDA.

项目摘要 这项赠款提案的目的是推进新型大环胡椒的临床前发展，即 Orynotide™MTD12813，用于治疗多药耐药（MDR）革兰氏阴性细菌感染，并与 最初的重点是由碳苯甲酸肠杆菌（CRE）引起的感染。出现 多种CRE病原体的感染造成了紧急的公共卫生威胁，因为碳青霉烯是 由MDR细菌病原体的越来越多的升高引起的感染药物的药物。只有两个物种， 肺炎肺炎和大肠杆菌，估计每年140,000个医院感染。 仅美国，许多人都具有碳青霉烯耐药性。全球共识是新的预防和 迫切需要进行治疗策略，以应对不断增长的MDR细菌感染问题。 申请人，θ-防御素生物学领域的领导者正在通过开发orntotides，a响应这种需求 新的宿主指导的抗菌大环的结构和生物学生物启动 theta（θ）-Defensin的特性，大环肽仅在旧世界猴子中表达（但不是 人类）。利用θ-防御素的多效性宿主防御性能，我们制作了一个新颖的库 Orynotides包括几种在MDR革兰氏阴性败血症模型中非常有效的化合物。 HIT-LEAD研究将MTD12813确定为临床前发育的主要诺属候选者 MDR革兰氏阴性感染的阶层免疫治疗剂。在小鼠腹膜败血症模型中， MTD12813的单剂量给药非常有效（与伴随细菌的生存增强 清除）抵抗多种CRE-K菌株。肺炎和CRE-E。大肠杆菌，另外被证明是 由MDR活化杆菌引起的败血症有效。与病原体范围一致 MTD12813在体内活跃，我们表明肽的作用方式是免疫治疗的， 促进宿主介导的细菌清除，刺激吞噬作用和嗜中性粒细胞募集，而 调节原本失调的促炎细胞因子的水平。这些数据表明MTD12813是 一种新型免疫治疗剂有效治疗革兰氏阴性细菌病原体。胡椒 容易制造（手头〜1.5 g），在人血浆中高度稳定，全血，对细菌的抗性 蛋白酶，当通过多种途径管理时，可容忍良好。在拟议的研究中，我们将进步 MTD12813的临床前表征。 AIM 1研究将包括生产GLP MTD12813和其他 关键试剂，药代动力学（PK）和PK/药效分析以及ADME研究。 AIM 2将集中精力 关于在细胞和分子水平上作用的照明机制。 AIM 3目标将包括临床前 大鼠和小猎犬犬的非GLP安全性和有毒动力学研究，免疫原性评估，发育 抗体抗体评估，并通过正式的GLP安全研究结束。这些目的的目的是 推进MTD12813的临床前开发，以向FDA提交IND。