Preclinical development of teixobactin, a new antibiotic

新型抗生素teixobactin的临床前开发

基本信息

批准号：
8903692
负责人：
Dallas Hughes
金额：
$ 74.97万
依托单位：
NOVOBIOTIC PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903692
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 Environment Evaluation Exposure to Fermentation G-Quartets Goals Gram-Positive Bacteria Half-Life Hospitals Human In Vitro Infection Lead Lipid III Lipids Liver Lung Metabolic 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 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 public health relevance sugar undecaprenyl pyrophosphate

项目摘要

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，作为治疗多种由细菌引起的感染的治疗剂。该第二阶段项目的目标是进行 teixobactin 的临床前开发，以便后续的 IND 研究能够利用占所有微生物的 99% 的未培养细菌来生产微生物的初始生长。 Teixobactin 是一种不寻常的缩酚酸肽，含有 enduracididine， Teixobactin 是一种新型肽聚糖合成抑制剂的第一个成员，我们发现该化合物没有针对脂质 II（肽聚糖前体）和脂质 III（磷壁酸前体）产生耐药性。它与十一异戊二烯基-PP-糖结合，与后来的脂质相反，该糖尚未被修饰。 II-D-Ala-D-Ala 可修饰形式是万古霉素的靶标，这种独特的作用模式与两个重要靶标（两者都不是蛋白质）结合，解释了 Teixobactin 缺乏针对广泛耐药性的产生。一系列革兰氏阳性细菌 - 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。 Teixobactin 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，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，包括扩大的微生物学研究。 Teixobactin 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、明确的批准途径和广泛的临床应用。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。该项目的结果将产生一种可进入 IND 研究的治疗先导候选药物。