AI-3 Inhibitors as treatment for bacterial infections

描述（由申请人提供）：细菌通过称为群体感应的信号系统相互通信。近年来已经证明，这种复杂的通信系统不仅可以包括细菌产生的信号，而且还可以包括宿主来源的信号，以控制致病物种中毒力基因的表达。这项提案结合了五个实验室的专业知识，开发出损害细菌群体感应的化合物。通过靶向群体感应，我们降低了抗性发展的可能性，因为它不是一个必要的生物过程，因此负选择压力将是次要的。我们已经确定了一种有前途的化合物，抑制肠出血性大肠杆菌的毒力。大肠杆菌和沙门氏菌属物种引起许多食物中毒综合征，以及土拉热弗朗西丝菌，通过干扰群体感应引起土拉菌病。由于存在广泛保守的膜结合受体蛋白，这三种不同的生物体以及潜在的许多其他生物体都可以被单一化合物靶向。初步数据表明，这种化合物在皮摩尔浓度范围内对细菌系统具有特异性，对宿主没有明显的不良影响。除了单一的化合物，我们有重要的初步数据，一些替代不同的化合物也已确定，并可能进一步发展。我们的财团拥有合理开发这种或替代化合物的专业知识，使其成为有效的广谱毒力抑制剂，使细菌无害。

DESCRIPTION (provided by applicant): Bacteria communicate with each other via a system of signals known as quorum sensing. In recent years it has been demonstrated that this complex system of communication can include not just bacterial produced signals, but also host derived signals to control gene expression of virulence in pathogenic species. This proposal combines the expertise of five laboratories to develop compounds that compromise bacterial quorum sensing. By targeting quorum sensing we decrease the possibility of the development of resistance as it is not an essential biological process and thus negative selective pressure will be minor. We have identified a promising compound that inhibits the virulence of enterohemorrhagic E. coli and Salmonella species causing numerous food poisoning syndromes, as well as Francisella tularensis, the causative agent of tularemia by interfering with quorum sensing. These three diverse organisms, and potentially many others, can all be targeted by a single compound due to the presence of a widely conserved membrane bound receptor protein. Preliminary data suggests that this compound is specific for bacterial systems at concentrations in the picomolar range and has no obvious adverse effects on the host. In addition to the single compound that we have significant preliminary data for a number of alternative distinct compounds have also been identified and may be further developed. Our consortium contains the expertise to rationally develop this or an alternative compound into effective broad-spectrum inhibitor of virulence rendering the bacteria harmless.