Novel Agents to Prevent Urinary Tract Infections

预防尿路感染的新型药物

• 批准号: 8978407
• 负责人: Marnie L Peterson
• 金额: $ 18.73万
• 依托单位: HENNEPIN LIFE SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-25 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8978407
• 关键词: Accounting; Acute; Adherence; Animal Model; Anti-Infective Agents; Antibiotic Resistance; Antibiotic-resistant organism; Antibiotics; Bacteria; Bacterial Infections; Bacterial Vaginosis; Biological Factors; Biological Models; Biological Sciences; Biotechnology; Bladder; Candidiasis; Catheterization; Catheters; Characteristics; Chronic; Cosmetics; Cross Infection; Development; Disease; Dose; Enterobacteriaceae; Enterococcus faecalis; Environment; Epithelial Cells; Evaluation; Fatty Acids; Food; Foreign Bodies; Frequencies; Gel; Genitourinary system; Gram-Positive Bacteria; Growth; Healthcare; Hospitals; Human; In Situ; In Vitro; Incidence; Individual; Indwelling Catheter; Infection; Infection prevention; Inflammation; Inflammatory; Iowa; Klebsiella pneumonia bacterium; Lactobacillus; Length; Long-Term Care; Microbe; Microbial Biofilms; Modeling; Mus; NIH Program Announcements; Organism; Prophylactic treatment; Pseudomonas aeruginosa; Recording of previous events; Research Personnel; Resistance; Role; Safety; Severities; Sexually Transmitted Diseases; Silicones; Small Business Innovation Research Grant; Staphylococcus aureus; Testing; Therapeutic; Tissues; Tube; Universities; Urinary tract; Urinary tract infection; Vagina; Woman; antimicrobial; bacterial adhesin receptor; base; catheter associated UTI; cost; glycerol monolaurate; human disease; improved; in vivo; innovation; killings; microbial; microbicide; nonhuman primate; novel; pathogen; prevent; public health relevance; quorum sensing; technology development; urinary

 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.

 描述（由申请人提供）：我们联合收割机结合了两名研究人员的优势，一名来自爱荷华州大学，另一名来自生物技术公司Hennepin Life Sciences（HLS），以开发一种暴露前粘膜治疗剂（PEMT），以降低导管相关尿路感染（CTTI）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，以减少这两种类型的感染。已初步证明，使用鼠膀胱炎模型，甘油单月桂酸酯（GML）作为5%非水凝胶在体外以及在膀胱和体内硅胶管（导管材料）上抑制细菌生长。正如在FDA提交的HLS pre-IND文件中所指出的，在人类泌尿生殖道中使用5% GML凝胶没有安全性问题;在女性中，5% GML凝胶减少了导致性传播感染、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，双重作用抗感染5% GML凝胶（微生物和宿主靶向）可用作PEMT，以降低膀胱和原位导管上细菌生长的频率和严重程度，从而预防膀胱炎。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5-10%的居民有>30天的留置导管。在我们计划的研究中，我们研究了GML在体外异物上和体内尿路中抑制肠杆菌科、铜绿假单胞菌、金黄色葡萄球菌、粪肠球菌生长的能力。我们的研究是高度创新的，因为我们寻求开发一种低成本，有效的，预防性的尿路感染。5%GML凝胶的使用为开发杀微生物剂提供了一种创新方法，因为该凝胶可抑制细菌感染并减少炎症环境。尿道炎的炎症可导致受损个体的组织损伤和作为细菌粘附素受体的宿主分子的暴露。尽管进行了广泛的研究，但未观察到对任一GML的微生物耐药性;这可能是由于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凝胶杀灭UTI病原体和预防硅胶导管定植的体外研究。具体目标2。评价5%GML凝胶在鼠抗真菌性口腔炎模型中对细菌病原体的有效性。