Preclinical development of teixobactin, a new antibiotic

 描述（由申请人提供）：该项目的长期目标是开发一种新型抗微生物剂--替沙菌素，用于治疗由以下原因引起的各种感染： 革兰氏阳性病原体感染该II期项目的目标是进行替沙菌素的临床前开发，以实现后续IND研究。NovoBiotic一直在利用占所有微生物99%的未培养细菌生产次级代谢产物。微生物在其自然环境中在扩散室中的初始生长使得能够进行随后的体外培养。Teixobactin是一种不寻常的缩肽，含有苯丙氨酸，甲基和4-D-氨基酸，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）。它与十一异戊二烯基-PP-糖结合，这些糖不知道被修饰，而不是后来的脂质II-D-Ala-D-Ala可修饰形式，万古霉素的靶标。这种独特的作用模式，结合两个基本目标，这两个都不是一个蛋白质，解释了缺乏耐药性的发展。泰克菌素对多种革兰氏阳性菌具有强效活性，包括金黄色葡萄球菌、肺炎链球菌、炭疽杆菌、结核分枝杆菌、粪肠球菌和大肠杆菌。屎室它对这些病原体的耐药形式具有活性，包括耐甲氧西林S。金黄色葡萄球菌（MRSA）和万古霉素耐药肠球菌。Teixobactin在鼠MRSA败血症和大腿感染模型中高度有效，并且针对S.肺炎在肺部感染模型。在本项目中，我们将完成替沙菌素的关键非GLP研究。将进行一系列体外和体内研究，包括扩大的微生物试验、毒性、药代动力学研究和体内疗效。替沙菌素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，明确的批准途径和大量患者人群。我们还将在医院获得性或呼吸机相关性细菌性肺炎（HABP/VABP）和肠球菌性心内膜炎的动物模型中测试该化合物，这些疾病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准备进入IND研究的治疗领先候选人。

 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.