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（由申请人提供）：该项目的长期目标是开发一种新型抗菌剂，teixobactin，作为治疗多种由 由革兰氏阳性病原体引起。该二期项目的目标是进行 teixobactin 的临床前开发，以实现后续的 IND 研究。 NovoBiotic 一直在利用占所有微生物 99% 的未培养细菌来生产次级代谢产物。微生物在自然环境中的扩散室中的初始生长使得后续的体外培养成为可能。 Teixobactin 是一种不寻常的缩酚肽，含有恩尿酸苷、甲基苯丙氨酸和 4-D-氨基酸，是新型肽聚糖合成抑制剂中的第一个成员。我们没有看到对该化合物产生耐药性。 Teixobactin 靶向脂质 II（肽聚糖的前体）和脂质 III（磷壁酸的前体）。它与十一碳烯基-PP-糖结合，而十一碳二烯基-PP-糖尚未被修饰，这与后来的脂质 II-D-Ala-D-Ala 可修饰形式（万古霉素的目标）相反。这种独特的作用模式与两个重要靶点结合，但两者都不是蛋白质，这解释了为何没有产生耐药性。 Teixobactin 对多种革兰氏阳性菌具有有效活性，包括金黄色葡萄球菌、肺炎链球菌、炭疽杆菌、结核分枝杆菌、粪肠球菌和屎肠球菌。它对这些病原体的耐药形式具有活性，包括耐甲氧西林金黄色葡萄球菌 (MRSA) 和耐万古霉素肠球菌。 Teixobactin 在小鼠 MRSA 败血症和大腿感染模型中以及在肺部感染模型中对肺炎链球菌非常有效。在这个项目中，我们将完成teixobactin的关键非GLP研究。将进行一系列体外和体内研究，包括扩大的微生物测试、毒性、药代动力学研究和体内功效。泰克巴汀最简单的临床适应症是急性细菌性皮肤和皮肤结构感染（ABSSSI），因为它对引起这种疾病的关键病原体具有高效力、明确的批准途径以及大量的患者群体。我们还将在医院获得性或呼吸机相关细菌性肺炎（HABP/VABP）和肠球菌性心内膜炎的动物模型中测试该化合物，这些动物模型通常没有可靠的治疗选择。生产优化将提高化合物的产量，以支持产品开发。该项目的结果将产生一种治疗先导候选药物，准备进入 IND 研究。