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

TP-217作为一种高效、广谱抗生素的开发

• 批准号: 8660026
• 负责人: Trudy Hope Grossman
• 金额: $ 48.16万
• 依托单位: CUBRC, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660026
• 关键词: ABCB1 gene; Address; Adverse effects; Aerosols; Aftercare; Ames Assay; Animals; Anti-Bacterial Agents; Antibiotics; Appearance; Autopsy; Bacteria; Biological Assay; Biological Availability; Blood specimen; Buffers; Categories; Cells; Clinical; Clinical Chemistry; Coagulation Process; Data; Databases; Development; Disease; Dosage Forms; Dose; Dose Fractionation; Doxycycline; Drug Controls; Drug Formulations; Drug Kinetics; Drug resistance; Engineering; Excipients; Fasting; Francisella tularensis; Heavy Metals; Hematology; Hepatocyte; High Pressure Liquid Chromatography; Histopathology; Human; Implant; In Vitro; Incidence; Infection; Intention; Investments; Ions; Lead; Licensure; Liver Microsomes; Lung; Macaca fascicularis; Mammalian Cell; Marketing; Medical; Metabolic; Methodology; Microbe; Micronucleus Tests; Modeling; Monitor; Monkeys; Motor Activity; Multi-Drug Resistance; Mus; Mutation; National Institute of Allergy and Infectious Disease; National Security; Ophthalmology; Oral; Organ Weight; Pan Genus; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Plasma Proteins; Pneumonic Plague; Prophylactic treatment; Protein Binding; Protocols documentation; Public Health; Qualifying; Rattus; Recovery; Regulation; Residual state; Resistance; Respiratory Tract Infections; Rotation; Running; Safety; Sampling; Sodium Heparin; Solid; Solubility; Solutions; Solvents; Spleen; Staphylococcal Infections; Survival Analysis; Telemetry; Testing; Tetracyclines; Therapeutic; Tissues; Titrations; Toxic effect; Toxicokinetics; Toxicology; Tularemia; Urinalysis; Work; Yersinia pestis; aerosolized; analog; analytical method; biodefense; biothreat; drug development; genotoxicity; good laboratory practice; in vivo; methicillin resistant Staphylococcus aureus; mortality; mouse model; pathogen; pre-clinical; resistance mechanism; standard of care; therapy development

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.

描述（由申请人提供）：尽管近年来投入了大量资金，但针对 NIAID A、B 和 C 类优先药物的强有力的医疗对策仍然稀缺。除了可用作生物武器的细菌构成的威胁之外，革兰氏阳性和革兰氏阴性病原体中多重耐药性的发生率不断增加也引起了许多担忧，因为上市的针对这些病原体的抗生素数量有限，而且缺乏能够覆盖药物开发管道的新抗生素。除了传统细菌公共卫生威胁中令人震惊的耐药性之外，优先药物自然或通过工程获得对当前疗法的耐药性的可能性也是一个严重威胁。因此，对多种敏感和耐药生物威胁病原体具有活性的广谱抗生素将成为雾化攻击期间经验性治疗和保护性预防的宝贵补充。多重耐药微生物被认为对美国公共卫生和国家安全构成重大威胁。 拟议的研究旨在推进 TP-271 的临床开发，用于治疗由易感和耐药的 NIAID A、B 和 C 类生物威胁和公共卫生病原体引起的呼吸道感染。针对肺鼠疫（死亡率高达 60%）和 CABP（例如耐甲氧西林金黄色葡萄球菌）的治疗和暴露后预防是最初的目标适应症。然而，考虑到 TP-271 的广谱抗菌活性，预计 TP-271 将能够抵御许多其他生物防御威胁。为了证实这一点，拟议的工作还将研究 TP-271 对小鼠土拉弗朗西斯菌的功效。一旦 FDA 最终获得许可，我们的目的是继续建立临床安全数据库，并扩大 TP-271 用于其他严重呼吸道感染的批准范围，包括其他 A 类和 B 类病原体，例如土拉杆菌。为了支持 TP-271 向 IND 方向发展，提出了一项临床前计划：1) 评估黑猩猩的口服生物利用度； 2) 在肺鼠疫小鼠模型中证明了疗效并优化了剂量； 3) 在兔热病小鼠模型中证明了功效； 4) 在MRSA感染的小鼠模型中检查TP-271的PK/PD； 5) 收集 GLP、IND 数据以支持多个物种和体外筛选的安全性。