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: 7815787
• 负责人: SCOTT J. HULTGREN
• 金额: $ 47.43万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7815787
• 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800万门诊就诊，估计每年的费用超过25亿美元。最常见的患者是女性，一生中有50%的机会发生急性UT感染（UTI），大多数由尿路致病性大肠杆菌（UPEC）引起。复发是一个常见的问题。出现急性UTI首次发作的女性有25-44%的机会在六个月内发生第二次发作，3%的机会在六个月内发生三次发作。由于这种感染引起的相当大的发病率，高复发率和细菌抗生素耐药性的发病率上升，新的治疗策略是必要的。UPEC产生含有甘露糖结合FimH尖端粘附素的1型皮利。在膀胱中，FimH介导细菌侵入浅表小面细胞。在这些细胞内，UPEC快速复制，形成生物膜样的细胞内细菌群落（IBC）。在IBC扩散后，UPEC扩散到邻近的细胞并重复循环，从而解释了单个细菌如何能够快速扩张并获得立足点并在UT中引起疾病。急性IBC级联的一个结果是形成静止的细胞内储库（QIR），其不能被抗生素治疗清除，可以持续数月，并且可以播种新一轮的感染。我们已经确定了FimH-甘露糖相互作用的结构基础和菌毛组装的机制。这些知识形成了合理设计化合物的基础，这些化合物通过干扰关键的宿主-病原体相互作用来阻断细菌定殖、IBC形成和感染。为应对挑战赠款15-DK-103而资助这项提案将大大加强我们为治疗UTI寻找替代策略的努力，这在面临抗生素耐药性和复发的情况下至关重要。使用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），其功能是通过防止IBC级联中的细菌扩增来阻断疾病。我们还设计和生产了阻止菌毛组装的杀菌毛剂。将评价最佳抑制剂的药物样性质，包括药代动力学、生物利用度和潜在毒性，并将在大量体外试验和我们的体内小鼠模型中评估其阻断毒力的功效。 公共卫生关系：合理设计，合成和测试1型菌毛FimH粘附素抑制剂的有效性的资助将大大增强我们寻找治疗尿路感染的替代策略的努力，尿路感染是人类最常见的感染之一。这是特别重要的，因为抗生素耐药性上升和高UTI复发率，否则健康的女性。