Preclinical development of teixobactin, a new antibiotic

 描述(申请人提供)：该计划的长期目标是开发一种新的抗菌剂teixobactin，使其成为一种治疗多种感染的药物 被革兰氏阳性病原体感染。该第二阶段项目的目标是进行替克生的临床前开发，以使后续的IND研究成为可能。新生物公司一直在利用未培养的细菌生产次生代谢物，这些细菌占所有微生物的99%。微生物在其自然环境中的扩散室中的初始生长使随后的体外培养成为可能。Teixobactin是一种含有耐尿酸、甲基苯丙氨酸和4-D-氨基酸的特殊多肽，是一类新的肽聚糖合成抑制剂的第一个成员。我们没有看到对这种化合物的耐药性发展。Teixobactin针对的是肽多聚糖的前体脂质II和磷壁酸的前体脂质III。它与十一碳烯基-PP-糖结合，而不是后来的脂类II-D-ALA-D-ALA可修饰形式，后者是万古霉素的靶标。这种独特的作用模式与两个基本靶点结合，这两个靶点都不是蛋白质，这解释了为什么缺乏耐药性发展。Teixobactin对多种革兰氏阳性菌--金黄色葡萄球菌、肺炎链球菌、炭疽杆菌、结核分枝杆菌、粪肠球菌和粪肠球菌有很强的抗菌活性。它对这些病原体的耐药形式具有活性，包括甲氧西林耐药金黄色葡萄球菌(MRSA)和万古霉素耐药肠球菌。在小鼠MRSA败血症和大腿感染模型中，teixobactin非常有效，在肺部感染模型中，teixobactin对肺炎链球菌有效。在这个项目中，我们将完成替克巴汀的关键的非GLP研究。将进行一系列的体外和体内研究，包括扩大的微生物测试、毒性、药代动力学研究和体内疗效。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)，因为它对导致这种疾病的关键病原体具有很高的效力、明确的批准途径和大量的患者。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，在这些动物模型中，通常没有可靠的治疗选择。生产优化将提高化合物的产率，为产品开发提供支持。该项目的结果将产生一位准备进入IND研究的治疗候选药物。

 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.