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: 8278486
• 负责人: Trudy Hope Grossman
• 金额: $ 52.11万
• 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/8278486
• 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）：尽管近年来进行了大量投资，但解决NIAID A、B和C类优先因子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所构成的威胁外，革兰氏阳性和革兰氏阴性病原体中多重耐药性的发生率日益增加引起了许多关切，这是因为市场上对这些病原体具有活性的抗生素数量有限，而且缺乏新的抗生素，将在药物开发管道中提供覆盖。除了传统细菌对公共卫生的威胁中令人震惊的耐药性水平外，优先药物对当前疗法天然或通过工程获得耐药性的可能性是一个严重的威胁。因此，具有针对多种敏感和耐药生物威胁病原体的活性的广谱抗生素将是雾化攻击期间经验性治疗和保护性预防的有价值的补充。耐多药微生物被认为是对美国公共卫生和国家安全的重大威胁。 拟定研究旨在推进TP-271临床开发，用于治疗由敏感和耐药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（与高达60%的死亡率相关）和CABP（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，鉴于TP-271的广谱抗菌活性，预计TP-271将保护免受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对小鼠中土拉弗朗西斯菌的有效性。一旦FDA最终获得许可，其目的是继续建立临床安全性数据库，并扩大TP-271用于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F。土拉热。为了支持TP-271向IND的发展，提出了一项临床前计划，该计划包括：1）在黑猩猩中评价口服生物利用度; 2）在肺鼠疫小鼠模型中证明疗效并优化给药; 3）在兔热病小鼠模型中证明疗效; 4）在MRSA感染小鼠模型中检查TP-271的PK/PD;和5）收集GLP、IND使能数据，以支持多个物种和体外筛选的安全性。