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: 7485731
• 负责人: Christie G. Brouillette
• 金额: $ 99.05万
• 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/7485731
• 关键词: 3-Dimensional; Acute; Address; Adjuvant; Aerosols; Agar; Anabolism; Animal Model; Animals; Anthrax disease; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Applied Research; Area Under Curve; Bacillus anthracis; Bacillus cereus; Bacillus subtilis; Bacteria; Binding; Bioavailable; Biological Assay; Biological Availability; Biological Warfare; Bioterrorism; Brain; Budgets; Cataloging; Catalogs; Catalytic Domain; Categories; Cells; Cessation of life; Ciprofloxacin; Class; Collection; Combined Modality Therapy; Commit; Complex; Computer Simulation; Computer software; Crystallization; Culture Media; Cytokeratin 8; Databases; Development; Diagnosis; Diagnostic; Disease; Doctor of Philosophy; Dose; Doxycycline; Drug Kinetics; Emerging Communicable Diseases; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Erythrocytes; Evaluation; Exposure to; Fetoprotein; Francisella tularensis; Funding; Generations; Glutamate-ammonia-ligase adenylyltransferase; Goals; Gram-Positive Bacteria; 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; Learning; Left; Lethal Dose 50; Letters; Libraries; Life; Literature; Liver; Lung; Maximum Tolerated Dose; Metabolic; Modeling; Mus; NAD synthase; National Institute of Allergy and Infectious Disease; New Mexico; Nicotinamide adenine dinucleotide; Numbers; Oral; Organism; Organism Cloning; Pathway interactions; Performance; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plague; Plasma; Plasma Proteins; Preclinical Drug Development; Principal Investigator; Prodrugs; Property; Protein Binding; Protocols documentation; Publishing; Purpose; Reporting; Research; Research Institute; Research Personnel; Resistance; Resistance development; Right-On; Risk; Roentgen Rays; Running; Score; Screening procedure; Sorting - Cell Movement; Structural Models; Structure; Structure-Activity Relationship; Symptoms; Synthesis Chemistry; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxicology; Toxin; Tularemia; Universities; Virulent; Yang; Yersinia pestis; absorption; antimicrobial; base; biodefense; chemical synthesis; combinatorial; cytotoxicity; design; dimer; drug discovery; enzyme structure; experience; expression cloning; in vivo; inhibitor/antagonist; interest; liver function; microbial; molecular modeling; monolayer; nicotinate mononucleotide; novel; pathogen; pre-clinical; prevent; programs; scale up; small molecule; success; therapeutic vaccine; vaccine development; 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：专门针对A类优先级细菌病原体开发的药物。炭疽，瘟疫和tularemia的感染目前已接受了现有的抗生素（例如环丙沙星和强力霉素）的治疗。然而，已知细菌生物恐怖剂的抗生素耐药菌菌株，使当前药物无效，此外，现有药物没有优化以治疗上述感兴趣的药物。该提案的长期目标是开发两个新型的抗菌药物类别，每种抗菌药物类别都经过优化，以对三个A类病原体，炭疽芽孢杆菌，Y. pestis或F. tolarensis引起的疾病有效。也就是说，针对这些病原体中的任何一种的选择治疗可能是相同的药物，因此在没有明确诊断的情况下可以立即有效治疗。这可能意味着生物恐怖袭击中生与死之间的差异，因为由于气雾剂暴露于这些药物而引起的症状是无法区分的。酶的烟酸单核苷酸腺苷转移酶（NAMNAT）和NAD+合成酶（NADS）催化NAD*生物合成的最后2个步骤，已被证明是对每个研究所研究的每个细菌的存活绝对必不可少的。可以单独使用的药物可以单独使用，也可以一起用于有效的组合疗法，可能不易受到抗性菌株的影响。我们开发了第一个报道的具有抗菌活性的NAD的小分子抑制剂，对细菌与人酶的选择性。每个靶标的细菌酶（每个目标三个；总共六个）将用于优化对所有三种生物同时有效的铅化合物。 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。同时，人类同源物将是设计策略的组成部分，因此可以同时设计抑制剂，以最小的人类毒性。实际上，已知细菌NAD和NAMNAT的选择性抑制剂。该U01程序的目标是生产一系列安全，口头生物利用和有效的高级铅化合物，并在既定的鼠模型中有效。相关性：进行的研究将导致用于治疗炭疽，瘟疫和tular症的新药。这些疾病是由三种最高风险的细菌生物恐怖剂，即炭疽芽孢杆菌，Y. pestis和F. tularensis引起的。