Discovery and Preclinical Development of Drugs for Anthrax, Plague and Tularemia

炭疽、鼠疫和兔热病药物的发现和临床前开发

• 批准号: 7676868
• 负责人: Christie G. Brouillette
• 金额: $ 98.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676868
• 关键词: Acute; Address; Aerosols; Agar; Anabolism; Animal Model; Animals; Anthrax disease; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Area Under Curve; Bacillus anthracis; Bacteria; Binding; Bioavailable; Biological Assay; Biological Availability; Bioterrorism; Brain; Budgets; Cataloging; Catalogs; Catalytic Domain; Categories; Cells; Cessation of life; Ciprofloxacin; Collection; Combined Modality Therapy; Complex; Computer Simulation; Computer software; Crystallization; Culture Media; Cytokeratin 8; Databases; Development; Diagnosis; Disease; Dose; Doxycycline; Drug Kinetics; Emerging Communicable Diseases; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Erythrocytes; Evaluation; Exposure to; Fetoprotein; Francisella tularensis; Funding; Glutamate-ammonia-ligase adenylyltransferase; Goals; Growth; Half-Life; Health Sciences; Hematopoietic; Hepatocyte; Homologous Gene; Homology Modeling; Human; Human Cell Line; In Vitro; Inbred BALB C Mice; Infection; Inhibitory Concentration 50; Kidney; Lead; Left; Lethal Dose 50; Letters; Libraries; Life; Ligase; Literature; Liver; Lung; Maximum Tolerated Dose; Metabolic; Modeling; Molecular Models; Mus; National Institute of Allergy and Infectious Disease; New Mexico; Oral; Organism; Organism Cloning; Performance; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plague; Plasma Proteins; Preclinical Drug Development; Property; Protein Binding; Protocols documentation; Publishing; Reporting; Research; Research Institute; Right-On; Roentgen Rays; Running; Screening procedure; Sorting - Cell Movement; Structural Models; Structure; Structure-Activity Relationship; Symptoms; Synthesis Chemistry; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Tularemia; Universities; Virulent; Yersinia pestis; absorption; animal efficacy; antimicrobial; base; biodefense; chemical synthesis; combinatorial; cytotoxicity; design; enzyme structure; expression cloning; high risk; in vitro testing; in vivo; inhibitor/antagonist; interest; liver function; microbial; molecular modeling; monolayer; nicotinate mononucleotide; novel; pathogen; pre-clinical; programs; resistant strain; scale up; small molecule; virtual

DESCRIPTION (provided by applicant): Project Summary: Drugs specifically developed against class A priority bacterial pathogens do not exist. Infections of anthrax, plague, and tularemia are currently treated with existing antibiotics such as ciprofloxacin and doxycycline. However, antibiotic-resistant strains of the bacterial bioterrorism agents are known, rendering current drugs ineffective, and furthermore, existing drugs are not optimized to treat the above agents of interest. The long term goal of this proposal is to develop two novel antibacterial drug classes, each of which has been optimized to be efficacious against disease caused by any of the three class A pathogens, B. anthracis, Y. pestis, or F. tularensis. That is, the treatment of choice against any of these pathogens could be the same drug, thus enabling immediate and efficacious treatment in the absence of a definitive diagnosis. This could mean the difference between life and death in a bioterrorism attack, since symptoms due to aerosol exposure to these agents would be indistinguishable. The enzymes nicotinate mononucleotide adenylyl- transferase (NAMNAT) and NAD+ synthetase (NADS), which catalyze the last 2 steps in NAD* biosynthesis, have been shown to be absolutely essential to the survival of every bacterium studied to date. Drugs developed against either could be used alone or together for an effective combination therapy that may be less susceptible to resistance strains. We developed the first reported small molecule inhibitors of NADS with antibacterial activity and selectivity for the bacterial versus human enzyme. Bacterial enzymes for each target (three per target; six in all) will be used to optimize lead compounds that are simultaneously effective against all three organisms. Within the funding period of this U01, inhibitors of NAMNAT and NADS will be developed through a reiterative cycle of molecular modeling and virtual screening against enzyme structures, medicinal chemistry/compound library development/structure-activity analysis, compound screening, and initial preclinical toxicology, pharmacokinetic, and animal efficacy against three Category A pathogens, B. anthracis, Y. pestis, and F. tularensis. At the same time, the human homolog will be an integral part of the design strategy so that inhibitors can be simultaneously designed for minimal human toxicity. In fact, selective inhibitors of bacterial NADS and NAMNAT are known. The goal of this U01 program is to produce a collection of advanced lead compounds that are safe, orally bioavailable, and efficacious in an established murine model. Relevance: The research conducted will lead to new drugs for the treatment of anthrax, plague, and tularemia. These diseases are caused by three of the highest risk bacterial bioterrorism agents, B. anthracis, Y. pestis, and F. tularensis.

描述(申请人提供)：项目摘要：不存在专门针对A类优先细菌病原体开发的药物。炭疽、鼠疫和图拉热症的感染目前用现有的抗生素治疗，如环丙沙星和多西环素。然而，细菌生物恐怖因子的抗药性菌株是已知的，使得当前的药物无效，而且现有的药物没有优化来治疗上述感兴趣的制剂。这项提议的长期目标是开发两类新的抗菌药物，每一类药物都经过优化，可以有效地对抗由三种A类病原体中的任何一种引起的疾病，即炭疽杆菌、鼠疫杆菌或图拉氏杆菌。也就是说，针对这些病原体的治疗选择可以是相同的药物，从而在没有明确诊断的情况下能够立即有效地治疗。这可能意味着生物恐怖袭击中的生死之别，因为暴露在这些毒剂下的气雾剂导致的症状将无法区分。到目前为止，催化NAD生物合成最后两步的烟酸单核苷酸腺苷转移酶(NAMNAT)和NAD+合成酶(NADS)对所有被研究的细菌的生存都是绝对必要的。针对这两种药物开发的药物可以单独使用，也可以联合使用，形成一种有效的联合疗法，可能不太容易受到耐药菌株的影响。我们开发了第一个报道的NADS小分子抑制剂，具有抗菌活性和对细菌与人类酶的选择性。每个目标的细菌酶(每个目标三个；总共六个)将被用来优化同时对所有三种生物有效的先导化合物。在U01的资助期内，NAMNAT和NADS的抑制剂将通过针对酶结构的分子建模和虚拟筛选、药物化学/化合物文库开发/结构-活性分析、化合物筛选以及对三种A类病原体(炭疽杆菌、鼠疫杆菌和图拉氏杆菌)的初步临床前毒理学、药代动力学和动物疗效的重复循环来开发。同时，人类同源基因将是设计策略的一个组成部分，这样就可以同时设计出对人体毒性最小的抑制剂。事实上，细菌NADS和NAMNAT的选择性抑制剂是已知的。该U01计划的目标是生产一系列先进的先导化合物，这些化合物在已建立的小鼠模型中是安全的、口服生物利用的和有效的。相关性：所进行的研究将导致治疗炭疽、鼠疫和图拉热症的新药。这些疾病是由三种风险最高的细菌生物恐怖因子引起的，即炭疽杆菌、鼠疫杆菌和图拉氏杆菌。