Use of Gallium to Prevent Pseudomonas Biofilm Formation

描述（由申请方提供）：生物膜形成在铜绿假单胞菌急性和慢性肺部感染的发病机制中很重要，降低了宿主防御的有效性和细菌对抗生素杀灭的敏感性。最近的证据表明，限制铁（Fe）的可用性防止铜绿假单胞菌生物膜的形成，并提高其对妥布霉素的敏感性。镓（Ca）是一种伊利亚族过渡金属，它会破坏许多细胞类型的铁代谢。我们已经表明，镓抑制结核分枝杆菌的生长和铁的收购。基于这些和新的数据，我们假设Ga可以破坏铜绿假单胞菌Fe的获取/代谢，从而破坏生物膜形成并增强对常规抗生素的敏感性。它还可以限制在铜绿假单胞菌感染部位与生物膜处于动态平衡的嗜酸性细菌的生长。因此，Ga可以成为针对铜绿假单胞菌生物膜的有效疗法。为了检验这些假设，将追求两个具体目标。首先，我们将确认和定义Ga抑制铜绿假单胞菌生物膜形成的机制，并确定Ga是否增强铜绿假单胞菌对常规抗生素的敏感性。这将使用两种体外铜绿假单胞菌生物膜模型进行。其次，我们将确定Ga对铜绿假单胞菌Fe获得和Fe依赖性基因调控的影响。我们将直接测量铜绿假单胞菌对Fe和Ga的获取，并表征Ga与其铁载体的相互作用。DNA微阵列技术将用于研究镓对铜绿假单胞菌基因调控的影响。这项工作的长期目标是开发一种利用Ga来预防和/或治疗铜绿假单胞菌生物膜和所导致的感染的方法。我们设想将Ga全身性和/或雾化肺部递送至铜绿假单胞菌感染的患者和/或用Ga浸渍气管内导管以防止通气患者中的生物膜形成。

DESCRIPTION (provided by applicant): Biofilm formation is important in the pathogenesis of acute and chronic infections of the lung by Pseudomonas aeruginosa, decreasing the effectiveness of host defenses and bacterial susceptibility to killing by antibiotics. Recent evidence shows that limiting iron (Fe) availability prevents P. aeruginosa biofilm formation and enhances its susceptibility to tobramycin. Gallium (Ca), a group IliA transition metal disrupts the Fe metabolism of many cell types. We have shown that Ga inhibits the growth and Fe acquisition by Mycobacterium tuberculosis. Based on these and new data, we hypothesize that Ga can disrupt P. aeruginosa Fe acquisition/metabolism, thereby disrupting biofilm formation and enhancing susceptibility to conventional antibiotics. It may also limit the growth of planktonic bacteria that would be in dynamic equilibrium with the biofilm at sites of P. aeruginosa infection. Thus, Ga could become a potent therapy against P. aeruginosa biofilms. To test these hypotheses, two specific aims will be pursued. First, we will confirm and define the mechanism whereby Ga inhibits P. aeruginosa biofilm formation and ascertain if Ga enhances the susceptibility of P. aeruginosa to conventional antibiotics. This will be done using two in vitro P. aeruginosa biofilm models. Second, we will determine the effect of Ga on P. aeruginosa Fe acquisition and Fe-dependent gene regulation. We will directly measure Fe and Ga acquisition by P. aeruginosa, as well as characterize the interaction of Ga with its siderophores. DNA microarray technology will be used to study the impact of Ga on P. aeruginosa gene regulation. The long-term goal of this work is to develop a means to utilize Ga for the prevention and/or treatment of P. aeruginosa biofilms and the infections that result. We would envision the systemic and/or aerosolized pulmonary delivery of Ga to P. aeruginosa-infected patients and/or impregnating endotracheal tubes with Ga to prevent biofilm formation in ventilated patients.