Preclinical development of teixobactin, a new antibiotic

新型抗生素teixobactin的临床前开发

• 批准号: 9000621
• 负责人: Dallas Hughes
• 金额: $ 74.09万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000621
• 关键词: Acute; Address; Amino Acids; Animal Model; Antibiotics; Antineoplastic Agents; Bacillus anthracis; Bacteria; Bacterial Infections; Bacterial Pneumonia; Binding; Biodistribution; Cell Wall; Clinical; Clostridium difficile; Collaborations; Depsipeptides; Development; Diffusion; Disease; Dose; Drug Kinetics; Drug resistance; Endocarditis; Enterococcus faecalis; Enterococcus faecium; Environment; Evaluation; Exposure to; Fermentation; G-Quartets; Goals; Gram-Positive Bacteria; Half-Life; Health; Hospitals; Human; In Vitro; Infection; Lead; Lipid III; Lipids; Liver; Lung; Modeling; Mus; Mycobacterium tuberculosis; National Cancer Institute; Nosocomial pneumonia; Peptide Hydrolases; Peptidoglycan; Pharmaceutical Preparations; Phase; Preparation; Production; Property; Proteins; Rattus; Regimen; Resistance; Resistance development; Rodent Model; Septicemia; Skin; Soil; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure; Teichoic Acids; Testing; Therapeutic; Thigh structure; Time; Tissues; Toxic effect; Toxicity Tests; Vancomycin; Vancomycin resistant enterococcus; Ventilator; animal efficacy; antimicrobial; base; combat; drug development; improved; in vivo; inhibitor/antagonist; killings; member; metabolic profile; methicillin resistant Staphylococcus aureus; microorganism; microorganism growth; mouse model; muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; mycobacterial; novel; pathogen; patient population; phenylalanine methyl ester; pre-clinical; product development; programs; sugar; undecaprenyl pyrophosphate

 DESCRIPTION (provided by applicant): The long-term goal of this program is to develop a novel antimicrobial, teixobactin, into a therapeutic for treating a wide range of infections caused by Gram-positive pathogens. The goal of this Phase II project is to perform preclinical development of teixobactin to enable subsequent IND studies. NovoBiotic has been exploiting uncultured bacteria that make up 99% of all microorganisms for production of secondary metabolites. Initial growth of microorganisms in a diffusion chamber in their natural environment enables subsequent cultivation in vitro. Teixobactin is an unusual depsipeptide that contains enduracididine, methyl-phenylalanine, and 4-D-amino acids and is the first member of a novel class of peptidoglycan synthesis inhibitors. We saw no resistance development to this compound. Teixobactin targets lipid II, precursor of peptidoglycan, and lipid III, precursor of teichoic acid. It binds to undecaprenyl-PP-sugars, which are not known to be modified, as opposed to a later lipid II-D-Ala-D-Ala modifiable form, the target of vancomycin. This unique mode of action, binding to two essential targets, neither of which is a protein, explains the lack of resistance development. Teixobactin has potent activity against a broad range of Gram-positive bacteria - Staphylococcus aureus, Streptococcus pneumoniae, Bacillus anthracis, Mycobacterium tuberculosis, Enterococcus faecalis and E. faecium. It is active against resistant forms of these pathogens, including methicillin resistant S. aureus (MRSA) and vancomycin-resistant enterococci. Teixobactin was highly efficacious in a murine MRSA septicemia and thigh infection models, and against S. pneumoniae in a lung infection model. In this project, we will complete key non-GLP studies of teixobactin. A set of in vitro and in vivo studies will be performed, including expanded microbiological testing, toxicity, pharmacokinetic studies, and in vivo efficacy. The simplest clinical indication for teixobactin is acute bacterial skin and skin structure infections (ABSSSI) due to its high potency against key pathogens causing this disease, well-defined path to approval, and a large patient population. We will also test the compound in animal models of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) and enterococcal endocarditis, where there are often no reliable options for treatment. Production optimization will increase the yield of the compound for supporting product development. The results of this project will produce a therapeutic lead candidate ready to enter IND studies.

 描述（由适用提供）：该程序的长期目标是将新颖的抗菌替代性远程脱脂蛋白开发成一种治疗，用于治疗引起的广泛感染 通过革兰氏阳性病原体。该II期项目的目的是进行远视双性恋的临床前开发，以实现后续的IND研究。 Novobirotic一直在利用未培养的细菌，占所有微生物的99％以生产继发代谢产物。微生物在其自然环境中的扩散室中的初始生长可以在体外进行随后的培养。 Teixobactin是一种不寻常的深度psipeptide，其中含有耐酰基蛋白，甲基 - 苯基丙氨酸和4-D-氨基酸，是新型肽聚糖合成抑制剂的第一个成员。我们没有看到这种化合物的耐药性发展。 Teixobactin靶向脂质II，肽聚糖的前体和Teichoic酸前体的脂质III。它与未经修饰的杂质肾上腺素基-PP-sugas结合，而不是后来的脂质II-d-d-ala-d-ala可修饰形式，即万古霉素的靶标。这种独特的作用方式与两个基本靶标结合，两者都不是蛋白质，都解释了缺乏抵抗力的发展。 Teixobactin具有潜在的活性，对革兰氏阳性细菌 - 金黄色葡萄球菌，肺炎链球菌，炭疽芽孢杆菌，结核分枝杆菌，结核菌，肠球菌粪便肠球菌和雌雄同体。它具有对这些病原体的耐药性形式的活跃，包括甲氧西林抗甲氧西葡萄球菌（MRSA）和抗性霉素肠球菌。 Teixobactin在鼠MRSA败血病和大腿感染模型中高效，在肺部感染模型中针对肺炎链球菌。在这个项目中，我们将完成对远非洲可爱的关键非GLP研究。将进行一组体外和体内研究，包括扩展的微生物测试，毒性，药代动力学研究和体内效率。电远黑骨的最简单临床指示是急性细菌皮肤和皮肤结构感染（ABSSI），因为它对关键病原体的高效力，导致这种疾病，确定的认可途径以及大量的患者人群。我们还将测试医院获得或呼吸机相关细菌肺炎（HABP/VABP）和肠内心内膜炎的动物模型中的化合物，那里通常没有可靠的治疗选择。生产优化将增加化合物的产量，以支持产品开发。该项目的结果将产生准备进入IND研究的治疗领位候选人。