AI-3 Inhibitors as treatment for bacterial infections

描述(由申请人提供)：细菌之间通过一种称为群体感应的信号系统进行交流。近年来的研究表明，这种复杂的通讯系统不仅可以包括细菌产生的信号，还可以包括宿主产生的信号来控制致病物种中毒力的基因表达。这项建议结合了五个实验室的专业知识，以开发损害细菌群体感应的化合物。通过针对群体感应，我们降低了产生抗性的可能性，因为这不是一个必要的生物过程，因此负选择压力将很小。我们已经确定了一种有希望的化合物，可以通过干扰群体感应来抑制引起大量食物中毒综合征的肠出血性大肠杆菌和沙门氏菌的毒力，以及图拉氏方济氏菌，图拉氏菌是图拉热症的病原体。由于存在一个广泛保守的膜结合受体蛋白，这三种不同的生物，以及潜在的许多其他生物，都可以被单一化合物靶向。初步数据表明，该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利影响。除了我们拥有的单一化合物的重要初步数据外，还确定了一些替代的不同化合物，并可能进一步开发。我们的联盟拥有专业知识，可以合理地将这种化合物或替代化合物开发成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.