Novel Agents to Prevent Urinary Tract Infections

 描述(由申请人提供)：我们结合了两名研究人员的力量，一名在爱荷华大学，另一名在生物技术公司Hennepin Life Sciences(HLS)，开发了暴露前粘膜治疗(PEMT)，以减少导管相关尿路感染(CAUTIs)的发生率。这些感染可能是急性和慢性的。我们的计划是开发一种PEMT来减少这两种类型的感染。单月桂酸甘油(GML)作为一种5%的非水凝胶，在体外、膀胱和体内的硅胶管(导管材料)上初步显示出抑制细菌生长的作用。正如在提交给FDA的HLS Pre-IND文件中指出的那样，在人类生殖道中使用5%GML凝胶没有安全问题；在女性中，5%GML凝胶可以减少引起性传播感染、细菌性阴道病和念珠菌病的阴道病原体。我们的主要假设是，双效抗感染5%GML凝胶(微生物和宿主靶向)可以用作PEMT，以降低膀胱和原位导管上细菌生长的频率和严重程度，以预防CAUTIs。这些是最常见的卫生保健相关感染，占医院相关感染的40%。此外，长期护理机构中有5%-10%的居民有30天留置导尿管。在我们计划的研究中，我们研究了GML在体外和体内对异物上肠杆菌科细菌、铜绿假单胞菌、金黄色葡萄球菌、粪肠球菌的生长抑制能力。我们的研究具有很高的创新性，因为我们寻求开发一种低成本、有效的CAUTIs预防方法。5%GML凝胶的使用为开发杀微生物剂提供了一种创新的方法，因为这种凝胶可以抑制细菌感染并减少炎症环境。CAUTIs中的炎症可能导致受损个体的组织损伤，以及作为细菌粘附素受体的宿主分子暴露。尽管进行了广泛的研究，但没有观察到微生物对这两种GML的耐药性；这可能是因为该化合物具有许多细菌靶标。提出了两个具体目标：具体目标1.评价5%GML凝胶对UTI病原体的杀灭作用和防止硅胶导管在体外定植的效果。具体目的2.在CAUTI小鼠模型中评价5%GML凝胶对细菌病原体的疗效。

 DESCRIPTION (provided by applicant): We combine the strengths of two researchers, one at the University of Iowa and one at a biotechnology company, Hennepin Life Sciences (HLS), to develop a pre-exposure mucosal therapeutic (PEMT) to reduce the incidence of catheter-associated urinary tract infections (CAUTIs). These infections may be acute and chronic. Our plan is to develop a PEMT to reduce both types of infections. Glycerol monolaurate (GML) as a 5% non-aqueous gel has been shown preliminarily to inhibit bacterial growth in vitro and in both bladders and on silicone tubes (catheter material) in vivo using a murine model of CAUTIs. As noted in a HLS pre-IND filing with FDA, there are no safety concerns for use of a 5% GML Gel in the human genitourinary tract; in women 5% GML Gel reduces vaginal pathogens that cause sexually-transmitted infections, bacterial vaginosis, and candidiasis. Our major hypothesis is that the dual-acting anti-infective 5% GML Gel (microbe and host-targeted) can be used as a PEMT to reduce the frequency and severity of bacterial growth in both bladders and on catheters in situ to prevent CAUTIs. These are the most frequent health care-associated infections and account for up to 40% of hospital-associated infections. In addition, 5-10% of residents in long-term care facilities have >30 day indwelling catheters. In our planned studies, we investigate the ability of GML to inhibit growth of Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis on foreign bodies in vitro and in the urinary tract in vivo. Our studies are highly innovative as we seek to develop a low cost, efficacious, prophylaxis for CAUTIs. The use of 5% GML Gel provides an innovative approach for development of a microbicide since the gel inhibits bacterial infection and reduces the inflammatory environment. Inflammation in CAUTIs can result in tissue damage in compromised individuals and the exposure of host molecules that act as receptors for bacterial adhesins. No microbial resistance to either GML has been observed despite extensive studies; this may result from the compound having numerous bacterial targets. Two specific aims are proposed: Specific Aim 1. Evaluation of 5% GML Gel killing of UTI pathogens and in preventing silicone catheter colonization in vitro. Specific Aim 2. Evaluation of 5% GML Gel efficacy against bacterial pathogens in a murine model of CAUTI.