Teixobactin Development for Anthrax

针对炭疽病的 Teixobactin 开发

• 批准号: 10192649
• 负责人: Dallas Hughes
• 金额: $ 99.64万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192649
• 关键词: Acute; Animal Model; Animals; Anthrax disease; Antibiotic Therapy; Antibiotics; Bacillus anthracis; Binding; Binding Proteins; Bioreactors; Cell Count; Cell Wall; Cells; Clinical; Clinical Research; Clinical Trials; Contracts; Cyclic GMP; Development; Dose; Drug Kinetics; Drug resistance; Drug usage; Engineering; Evaluation; Exposure to; Fermentation; Funding; Future; Goals; Gram-Positive Bacteria; Grant; Histopathology; Human; In Vitro; Infection; Inhalation; Length; Lipid III; Lipids; Lung; Manufacturer Name; Medical; Methods; Modeling; Monkeys; Mycobacterium tuberculosis; Onset of illness; Organ; Oryctolagus cuniculus; Pathogenicity; Peptidoglycan; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Plasma Proteins; Pneumococcal Infections; Preparation; Production; Program Development; Property; Proteins; Resistance; Resistance development; Running; Safety; Sampling; Septicemia; Serum; Skin; Source; Staphylococcus aureus; Structure; Teichoic Acids; Testing; Texas; Therapeutic; Tissues; Toxicology; Universities; Work; animal efficacy; animal rule; biothreat; combat; drug resistant pathogen; efficacy study; methicillin resistant Staphylococcus aureus; microbial; minimal inhibitory concentration; mutant; nonhuman primate; pathogen; preclinical development; resistance frequency; scale up; side effect; therapy development; therapy resistant; weapons

ABSTRACT The goal of this project is to continue developing teixobactin (TXB) as an antibiotic to combat weaponized anthrax. This work will be done in parallel to an ongoing preclinical development program, which is advancing TXB for treating infections caused by other serious pathogens such as methicillin resistant Staphylococcus aureus (MRSA). TXB has shown excellent efficacy in several animal models of infection, including a rabbit model of inhalation anthrax recently run at the University of Texas Medical Branch (Galveston, TX). Due to TXB’s unusual mechanism of action – binding two different bacterial cell wall targets, neither of which is a protein – TXB represents an example of a compound that is exceptionally free of resistance development and thus is an excellent candidate as a countermeasure for anthrax. The work in this grant will include the following Specific Aims: Aim 1 will provide at least 50 grams of non-cGMP teixobactin to fulfill all studies in the proposal. In addition, at least 200 grams of cGMP material will be produced at a contract manufacturer for planned future studies. Aim 2 will focus on the following studies to further understand TXB’s in vitro properties: (a) MIC testing against a panel of key B. anthracis isolates, including isolates resistant to current anthrax drugs; (b) determine B. anthracis resistance frequency to teixobactin; and (c) protein binding studies using rabbit, nonhuman primate (NHP), and human serum to determine free drug levels. Aim 3 will determine the minimal therapeutic TXB dose in the rabbit anthrax efficacy model, with associated pharmacokinetic (PK) profiling and histopathology. The information in Aim 3, in addition to the toxicology, safety and PK/PD studies being run in parallel with this project, will help inform NHP and human dosing. At the conclusion of this grant, TXB will be prepared to enter a GLP-compliant, NHP inhalation anthrax study and a Phase I clinical study, all in support of FDA approval for treating anthrax under the Animal Rule.

摘要