Development of TP-217 as a highly efficacious, broad-spectrum antibiotic for the

描述(由申请人提供)：尽管近年来进行了大量投资，但针对NIAID A、B和C类优先药物的强有力的医学对策仍然很少。除了可用作生物武器的细菌构成的威胁外，革兰氏阳性和革兰氏阴性病原体中多重耐药的发生率日益上升也引起了许多关注，这是因为上市的具有抗这些病原体活性的抗生素数量有限，而且缺乏将在药物开发管道中提供覆盖范围的新抗生素。除了传统细菌公共卫生威胁中令人震惊的抗药性之外，优先药物自然或通过工程获得对当前疗法的抗药性的可能性也是一个严重的威胁。因此，一种对多种敏感和耐药生物硫脲病原体具有活性的广谱抗生素将是在雾化攻击期间进行经验性治疗和保护性预防的有价值的补充。具有多重耐药性的微生物被认为是对美国公共健康和国家安全的重大威胁。 拟议的研究旨在将TP-271推向临床开发，用于治疗由敏感和耐药的NIAID A、B和C类生物制剂以及公共卫生病原体引起的呼吸道感染。最初的目标适应症是针对肺炎鼠疫和CABP(如耐甲氧西林金黄色葡萄球菌)的治疗和暴露后预防，肺炎鼠疫与高达60%的死亡率有关。然而，鉴于TP-271‘S具有广谱抗菌活性，预计TP-271将防御许多其他生物防御威胁。为了证实这一点，拟议的工作还将调查TP-271对小鼠图拉氏方济氏菌的疗效。一旦FDA最终获得许可，其意图是继续建立临床安全数据库，并扩大TP-271对其他严重呼吸道感染的批准，包括其他A类和B类病原体，如图拉氏杆菌。为了支持TP-271向IND的发展，已经提出了一项临床前计划，该计划1)评估在黑猩猩身上的口服生物利用度；2)证实在肺炎鼠疫小鼠模型上的有效性和优化剂量；3)在图拉雷血症小鼠模型上证明有效性；4)在MRSA感染的小鼠模型中检测TP-271的PK/PD；以及5)收集GLP、IND使能的数据，以支持多物种的安全性和体外筛选。

DESCRIPTION (provided by applicant): Despite significant investment in recent years, robust medical countermeasures to address the NIAID Category A, B, and C priority agents remain scarce. In addition to the threat posed by bacteria that can be used as bioweapons, the increasing incidence of multidrug-resistance among gram-positive and gram-negative pathogens has raised many concerns, due to the limited number of marketed antibiotics with activity against these pathogens and a dearth of new antibiotics that will provide coverage in the drug development pipeline. In addition to the alarming levels of resistance among traditional bacterial public health threats, the possibility for priority agents to acquire resistance to current therapies either naturally or via engineering is a serious threat. Consequently, a broad-spectrum antibiotic with activity against multiple susceptible and drug-resistant biothreat pathogens would be a valued addition to the armamentarium for empiric treatment during an aerosolized attack and for protective prophylaxis. Multidrug-resistant microbes are considered a substantial threat to US public health and national security. The proposed studies are aimed at advancing TP-271 toward clinical development for the treatment of respiratory infections caused by susceptible and drug-resistant NIAID Category A, B and C biothreat and public health pathogens. Treatment and post-exposure prophylaxis against pneumonic plague - which is associated with up to 60% mortality - and CABP (such as methicillin-resistant Staphylococcus aureus) are the initially targeted indications. However, given TP-271's broad-spectrum antibacterial activity, it is expected that TP-271 will protect against many other biodefense threats. To substantiate this, the proposed work will also investigate the efficacy of TP-271 against Francisella tularensis in mice. Once licensure by the FDA ultimately occurs, the intention is to continue to build a clinical safety database and expand the approval of TP-271 for other serious respiratory infections, including additional Category A and B pathogens such as F. tularensis. To support the development of TP-271 toward IND, a preclinical plan has been proposed which 1) evaluates oral bioavailability in chimpanzees; 2) demonstrates efficacy in a mouse model of pneumonic plague and optimizes dosing; 3) demonstrates efficacy in a mouse model of tularemia; 4) examines the PK/PD of TP-271 in a murine model of MRSA infection; and 5) collects GLP, IND-enabling data to support safety in multiple species and in in vitro screens.