Development of furanones for treatment of anthrax

描述（由申请方提供）：炭疽芽孢杆菌（BA）是CDC A类病原体。由于吸入性炭疽的高死亡率，尽管抗生素治疗，需要新的治疗方法。提出的工作重点是群体感应（QS）的中断作为一种方法来干扰BA细胞-细胞通信。我们的初步工作表明，luxS突变体BA细胞不产生AI-2，并且生长减少。两（2）种天然存在的呋喃酮QS抑制剂和2种合成抑制剂阻止BA生长，并减少毒素产生。呋喃酮在治疗有效的浓度下对巨噬细胞没有抑制作用。基于这个目标（QS）和4 BA抑制剂，我们建议解决他们的效用作为新的治疗炭疽。在目标1中，我们将评估巨噬细胞培养物和小鼠中的毒性，以确定可使用的最大安全水平。在目标2中，我们将开始使用Sterne（疫苗）菌株34 F2首先在巨噬细胞中进行有效性试验，然后在实验激发小鼠中进行有效性试验。将用LD 50和10或100 x LD 50剂量激发小鼠，我们将根据所用呋喃酮、剂量和时间评估疾病和存活率。环丙沙星或达托霉素将被用作对照，并与呋喃酮的协同作用进行了探索。在目标3中，将在ABL 3设施中使用毒性BA孢子在小鼠模型中检测先导化合物。在最初的研究中，孢子将皮下注射。疗效参数定义如上。成功的试验可以导致人类的I期研究和非人类灵长类动物的治疗研究。

DESCRIPTION (provided by applicant): Bacillus anthracis (BA) is a CDC Category A agent. Because of the high mortality due to inhalational anthrax despite antibiotic therapy, new therapeutics are needed. The work proposed focuses on interruption of quorum sensing (QS) as an approach to interfering with BA cell-cell communication. Our preliminary work shows that luxS mutant BA cells do not produce AI-2, and have diminshed growth. Two (2) naturally occuring furanone QS inhibitors and 2 synthetic inhibitors arrest BA growth, and diminish toxin production. The furanones are not inhibitory to macrophages in concentrations that are therapeutically effective. Based on this target (QS) and 4 BA inhibitors, we propose to address their utility as new therapies for anthrax. In Aim 1, we will assess toxicity in both macrophage cell culture and in mice to determine the maximum safe levels that can be used. In Aim 2, we will begin efficacy trials using the Sterne (vaccine) strain 34F2 first in macrophages, then in experimentally challenged mice. Mice will be challenged with LD50 and 10 or 100 x LD50 doses, and we will assess illness and survival based on furanone used, dose, and timing. Ciprofloxacin or daptomycin will be used as comparitors, and synergies with the furanones explored as well. In Aim 3, the lead compound will be tested in a mice model with virulent BA spores in an ABL3 facility. In initial studies, spores will be given subcutaneosly. Efficacy parameters will be defined as above. Successful trials can lead to phase I studies in humans, and treatment studies in non-human primates.