RATIONAL DESIGN OF MANNOSIDES FOR INHIBITION OF FIMH AND TREATMENT OF UTI

甘露糖苷抑制 FIMH 和治疗 UTI 的合理设计

• 批准号: 7938679
• 负责人: SCOTT J. HULTGREN
• 金额: $ 43.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938679
• 关键词: Acute; Adhesions; Affinity; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Adhesins; Bacterial Antibiotic Resistance; Binding; Biological Assay; Biological Availability; Biomass; Bladder; Cells; Chemicals; Clinical; Clinical Treatment; Communities; Disease; Drug Design; Drug Kinetics; Equipment; Escherichia coli Infections; Evaluation; Event; Face; Female; Funding; Future; Generations; Grant; Hemagglutination; Human; In Vitro; Incidence; Infection; Knowledge; Libraries; Life; Ligands; Mannose; Mannosides; Mediating; Methods; Microbial Biofilms; Modeling; Morbidity - disease rate; Mus; Organic Synthesis; Outcome; Outpatients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pilum; Population; Postdoctoral Fellow; Property; Recurrence; Resolution; Roentgen Rays; Route; Seeds; Site; Structure; Techniques; Testing; Therapeutic; Time; Toxic effect; Urinary tract; Urinary tract infection; Uropathogenic E. coli; Virulence; Virulence Factors; Visit; Wages; Woman; Work; base; career development; cost; design; dosage; efficacy testing; experience; in vitro Assay; in vivo; inhibitor/antagonist; interdisciplinary approach; pathogen; prevent; public health relevance; receptor binding; response; small molecule; treatment strategy

DESCRIPTION (provided by applicant): The urinary tract (UT) is a common site of infection in humans, with an estimated 8 million outpatient visits in the U.S. and an estimated cost exceeding $2.5 billion annually. The most frequent sufferers are women, with a 50% lifetime chance of developing an acute UT infection (UTI), the majority caused by uropathogenic Escherichia coli (UPEC). Recurrence is a common problem. Women who present with an initial episode of acute UTI have a 25-44% chance of developing a second and a 3% chance of experiencing three episodes within six months. Due to considerable morbidity caused by this infection, the high recurrence rate and the rising incidence of bacterial antibiotic resistance, new strategies for treatment are necessary. UPEC produce type 1 pili that contain the mannose binding FimH tip adhesin. In the bladder, FimH mediates bacterial invasion into superficial facet cells. Inside these cells, UPEC rapidly replicate forming biofilm-like intracellular bacterial communities (IBCs). Upon dispersal of the IBC, UPEC spread to neighboring cells and repeat the cycle thus explaining how single bacteria are able to rapidly expand and gain a foothold and cause disease in the UT. One outcome of the acute IBC cascade is the formation of quiescent intracellular reservoirs (QIRs) that are not cleared by antibiotic treatments, can persist for months, and can seed new rounds of infection. We have determined the structural basis of the FimH-mannose interaction and the mechanism of pilus assembly. This knowledge forms the basis for rational design of compounds that block bacterial colonization, IBC formation and infection, by interfering with critical host-pathogen interactions. Funding of this proposal in response to challenge grant 15-DK-103 will greatly enhance our efforts to find alternative strategies for treatment of UTI which is critical in the face of rising antibiotic resistance and recurrence. Using rational structure-based drug design and synthesis, we propose to develop high affinity mannose derivatives (mannosides) that function to block disease by preventing bacterial expansion in the IBC cascade. We also have designed and produced pilicides that block pilus assembly. The drug-like properties including pharmokinetics, bioavailability and potential toxicity of the best inhibitors will be evaluated and their efficacy in blocking virulence will be assessed in a multitude of in vitro assays and in our in vivo murine model. PUBLIC HEALTH RELEVANCE: This grant to rationally design, synthesize and test the efficacy of type 1 pilus FimH adhesin inhibitors will greatly enhance our efforts to find alternative strategies for treatment of urinary tract infections, one of the most common infections in humans. This is particularly important due to rising antibiotic resistance and high UTI recurrence rates in otherwise healthy females.

描述（由申请人提供）：尿路（UT）是人类常见的感染部位，在美国估计有800万门诊人次，估计每年花费超过25亿美元。最常见的患者是女性，一生中有50%的机会患上急性尿路感染（UTI），其中大多数是由尿路致病性大肠杆菌（UPEC）引起的。复发是一个常见的问题。首次出现急性尿路感染发作的妇女有25-44%的机会发展为第二次发作，3%的机会在六个月内经历三次发作。由于这种感染引起的相当高的发病率，高复发率和细菌抗生素耐药性的发生率上升，新的治疗策略是必要的。UPEC产生的1型菌毛含有甘露糖结合FimH尖端粘连素。在膀胱中，FimH介导细菌侵入浅表突细胞。在这些细胞内，UPEC迅速复制形成生物膜样细胞内细菌群落（IBCs）。随着IBC的扩散，UPEC扩散到邻近的细胞并重复这个循环，从而解释了单个细菌如何能够迅速扩张并在UT中站稳脚跟并引起疾病。急性IBC级联的一个结果是形成静止的细胞内储存库（qir），这些储存库不能被抗生素治疗清除，可以持续数月，并可能播下新一轮感染的种子。我们确定了fimh -甘露糖相互作用的结构基础和菌毛组装的机理。这些知识构成了合理设计化合物的基础，这些化合物通过干扰宿主-病原体的关键相互作用来阻止细菌定植、IBC形成和感染。为响应挑战基金15-DK-103，为该提案提供资金将大大加强我们寻找治疗尿路感染的替代策略的努力，这对于面对不断上升的抗生素耐药性和复发至关重要。通过合理的基于结构的药物设计和合成，我们建议开发高亲和力的甘露糖衍生物（甘露糖苷），通过阻止IBC级联中的细菌扩张来阻断疾病。我们还设计和生产了阻止菌毛组装的杀菌剂。将评估最佳抑制剂的药物样特性，包括药代动力学、生物利用度和潜在毒性，并通过大量体外试验和体内小鼠模型评估其阻断毒力的功效。