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（由申请人提供）： 项目概要： 不存在专门针对 A 类优先细菌病原体开发的药物。目前，炭疽、鼠疫和兔热病的感染是用现有的抗生素治疗的，例如环丙沙星和强力霉素。然而，细菌生物恐怖剂的抗生素抗性菌株是已知的，这使得现有药物无效，此外，现有药物没有针对治疗上述感兴趣的药物进行优化。该提案的长期目标是开发两种新型抗菌药物，每种药物均经过优化，可有效对抗由炭疽杆菌、鼠疫杆菌或土拉热杆菌这三种 A 类病原体中的任何一种引起的疾病。也就是说，针对任何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的治疗。这可能意味着生物恐怖袭击中生与死的区别，因为气溶胶暴露于这些物质所产生的症状是无法区分的。烟酸单核苷酸腺苷酸转移酶 (NAMNAT) 和 NAD+ 合成酶 (NADS) 催化 NAD* 生物合成的最后 2 个步骤，已被证明对迄今为止研究的每种细菌的生存至关重要。针对其中任何一种药物开发的药物可以单独使用或一起使用，以进行有效的联合治疗，这种治疗可能不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，具有抗菌活性以及对细菌酶和人类酶的选择性。每个目标的细菌酶（每个目标三种；总共六种）将用于优化同时有效对抗所有三种生物体的先导化合物。在该 U01 的资助期内，NAMNAT 和 NADS 的抑制剂将通过分子建模和酶结构虚拟筛选、药物化学/化合物库开发/结构活性分析、化合物筛选和初始临床前毒理学的重复循环来开发，针对三种 A 类病原体（炭疽芽孢杆菌、鼠疫耶尔森菌和土拉热杆菌）的药代动力学和动物功效。同时，人类同源物将成为设计策略的一个组成部分，以便可以同时设计抑制剂以将人类毒性降至最低。事实上，细菌NADS和NAMNAT的选择性抑制剂是已知的。 U01 项目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安全、口服生物可利用且有效。相关性：所进行的研究将带来治疗炭疽、鼠疫和兔热病的新药。这些疾病是由三种风险最高的细菌生物恐怖剂引起的：炭疽芽孢杆菌、鼠疫耶尔森菌和土拉热杆菌。