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

描述（由申请人提供）：项目概述：不存在专门针对A类优先细菌病原体开发的药物。炭疽、鼠疫和兔热病的感染目前用现有的抗生素如环丙沙星和多西环素治疗。然而，已知细菌生物恐怖剂的抗药性菌株，使得目前的药物无效，此外，现有的药物没有被优化以治疗上述感兴趣的试剂。该提案的长期目标是开发两种新型抗菌药物，每种抗菌药物都经过优化，可有效对抗由三种A类病原体B中的任何一种引起的疾病。anthracis，Y. pestis或F.土拉热。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地治疗。这可能意味着在生物恐怖主义袭击中生与死的区别，因为由于暴露于这些制剂的气溶胶引起的症状将无法区分。催化NAD* 生物合成中最后2个步骤的酶烟酸单核苷酸腺苷酰转移酶（NAMNAT）和NAD+合成酶（NADS）已被证明对迄今为止研究的每种细菌的存活绝对必需。针对这两种药物开发的药物可以单独使用，也可以一起使用，以进行有效的联合治疗，从而降低对耐药菌株的敏感性。我们开发了第一个报道的NADS的小分子抑制剂，具有抗菌活性和对细菌与人类酶的选择性。每个靶标的细菌酶（每个靶标三种;总共六种）将用于优化对所有三种生物体同时有效的先导化合物。在本U 01的资助期内，NAMNAT和NADS的抑制剂将通过分子建模和针对酶结构的虚拟筛选、药物化学/化合物库开发/结构-活性分析、化合物筛选以及针对三种A类病原体、B的初始临床前毒理学、药代动力学和动物疗效的循环开发。anthracis，Y. pestis和F.土拉热。与此同时，人类同源物将是设计策略的一个组成部分，以便抑制剂可以同时设计为最小的人类毒性。事实上，已知细菌NADS和NAMNAT的选择性抑制剂。该U 01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、口服生物利用度高且有效。相关性：所进行的研究将导致治疗炭疽、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B引起的。anthracis，Y.鼠疫杆菌和F.土拉热。

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.