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

基本信息

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
项目类别：
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

项目摘要

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）：尽管近年来投资大量投资，但解决NIAID A，B和C优先级代理的强大医疗对策仍然很少。除了细菌所带来的威胁可以用作生物武器外，革兰氏阳性和革兰氏阴性的病原体之间多药抗性的发生率的增加，由于对这些病原体的活性有限，针对这些新抗生素的活性以及在药物开发中覆盖的新抗生素的活性有限，因此引起了许多问题。除了传统的细菌公共卫生威胁之间的阻力令人震惊的水平外，优先级代理人自然或通过工程学获得对当前疗法的抵抗的可能性也是一个严重的威胁。因此，具有对多种易感和耐药性生物治疗病原体活性的广谱抗生素将是在雾化攻击和保护性预防时进行经验治疗的有价值的。抗多物质的微生物被认为是对美国公共卫生和国家安全的重大威胁。拟议的研究旨在将TP-271推进到临床开发中，以治疗由易感和耐药性NIAID类别A，B和C生物治疗和公共卫生病原体引起的呼吸道感染。针对肺炎鼠疫的治疗和暴露后预防 - 与高达60％的死亡率有关 - 和CABP（例如耐甲氧西林的金黄色葡萄球菌）是最初的靶向指示。但是，鉴于TP-271的广谱抗菌活性，预计TP-271将防止许多其他生物危险威胁。为了证实这一点，拟议的工作还将研究TP-271对弗朗西斯氏菌在小鼠中的疗效。一旦FDA的许可最终发生，其目的是继续建立临床安全数据库，并扩大TP-271的批准，以用于其他严重的呼吸道感染，包括其他类别A和B病原体，例如F. tolarensis。为了支持TP-271向IND的发展，已经提出了一个临床前计划，其中1）评估黑猩猩的口服生物利用度； 2）证明在肺炎鼠疫小鼠模型中的功效并优化给药； 3）证明了小鼠tularemia模型的功效； 4）在MRSA感染的鼠模型中检查了TP-271的PK/PD；和5）收集GLP，辅助数据，以支持多种物种和体外筛查的安全性。