Development of furanones for treatment of anthrax

描述(申请人提供)：炭疽芽孢杆菌(BA)是疾控中心A类药物。由于尽管使用抗生素治疗，吸入性炭疽病的死亡率很高，因此需要新的治疗方法。提出的工作重点是中断群体感知(QS)，作为干扰BA小区间通信的一种方法。我们的初步工作表明，LuxS突变的BA细胞不产生AI-2，并且生长减弱。两(2)个天然的呋喃酮QS抑制剂和两个合成的抑制剂抑制BA的生长，并减少毒素的产生。在治疗有效的浓度下，呋喃酮对巨噬细胞没有抑制作用。基于这一靶点(QS)和4种BA抑制剂，我们建议将它们作为炭疽病的新疗法。在目标1中，我们将评估巨噬细胞培养和小鼠的毒性，以确定可以使用的最大安全水平。在目标2中，我们将首先在巨噬细胞中使用Sterne(疫苗)菌株34F2进行疗效试验，然后在实验挑战的小鼠中进行。小鼠将接受LD50和10或100倍LD50剂量的挑战，我们将根据呋喃酮的使用、剂量和时机来评估疾病和生存。将使用环丙沙星或达托霉素作为对照，并探讨与呋喃酮类药物的协同作用。在目标3中，先导化合物将在ABL3设施中用带有有毒BA孢子的小鼠模型进行测试。在最初的研究中，孢子将被皮下给予。功效参数定义如上。成功的试验可能导致在人类身上进行I期研究，并在非人类灵长类动物上进行治疗研究。

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.