Acid Adaptation Targets for Eradication of Helicobacter pylori

根除幽门螺杆菌的酸适应目标

• 批准号: 9275334
• 负责人: George Sachs
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275334
• 关键词: Acclimatization; Acidity; Acids; Agmatine; Amoxicillin; Antibiotic Resistance; Antibiotics; Arginine; Bacteria; Bacterial Infections; Bicarbonates; Binding Sites; Biology; Buffers; Butyric Acids; Cadaverine; Carcinogens; Cell physiology; Childhood; Chronic; Clarithromycin; Clinical Trials; Complex; Consumption; Coupled; Crystallization; Cytoplasm; Cytoplasmic Tail; Decarboxylation; Development; Disease; Drug Targeting; Environment; Enzymes; Essential Amino Acids; Failure; Future; Gastric Acid; Gastric Adenocarcinoma; Gastric mucosa; Gastritis; Gene Cluster; Gene Targeting; Gerbils; Glutamates; Goals; Growth; Helicobacter Infections; Helicobacter pylori; Histamine-2 Receptor Antagonist; Human; Immune response; Infection; Investigation; Laboratories; Lead; Left; Lysine decarboxylase; Maintenance; Medicine; Membrane; Metronidazole; Modeling; Mono-S; Omeprazole; Organism; Oxidation-Reduction; Peptic Ulcer; Pharmaceutical Preparations; Phase; Population; Prevention; Process; Property; Proteins; Proteome; Proton Pump; Proton Pump Inhibitors; Protons; Regimen; Resistance; Risk; Risk Factors; Role; Stomach; Structure; Surface; System; Techniques; Testing; Ulcer; United States; Urea; Urease; Veterans; World Health Organization; antiporter; bacterial resistance; bactericide; base; carbonate dehydratase; compliance behavior; drug development; experimental study; falls; healing; high risk; improved; inhibitor/antagonist; malignant stomach neoplasm; mucosa-associated lymphoid tissue lymphoma; novel; novel therapeutics; pH Homeostasis; periplasm; protein function; protein protein interaction; public health relevance; resistance mechanism; response; sensor histidine kinase; success; therapy outcome

DESCRIPTION (provided by applicant): Helicobacter pylori infects the stomach of half of the world's population. This infection is a primary cause of peptic ulcer disease and a high risk factor for gastric cancer. Therefore, eradication of H. pylori infection leads to ulcer healing and lowers the risk of gastric cancer. Unil the discovery of H. pylori, it was thought that stomach acid presented an inhospitable environment for bacterial infection. However, H. pylori has uniquely developed the means of surviving and growing on the acidic surface of the human stomach, a process termed acid acclimation. Disruption of this process leads to loss of survival in acid; therefore, the components of this process would provide novel targets for eradication therapy. Current eradication therapies require the use of antibiotics along with acid-inhibitory drugs. The successful eradication by these therapies is decreasing because of increasing antibiotic resistance, resulting in a response rate of ~70% in the USA. The growth-dependent antibiotics clarithromycin or amoxicillin are not effective unless bacteria are in growth phase. Improving acid inhibition should improve therapeutic outcome. In the first aim, we hypothesize that inhibition of acid secretion increases the number of bacteria in growth phase, making them sensitive to growth-dependent antibiotics, necessitating the requirement for administration of acid-inhibitory compounds, in addition to antibiotics for successful eradication. The finding that slow omeprazole metabolizers respond with much improved acid control and effective eradication with omeprazole and amoxicillin alone, suggests that improved acid inhibition increases the sensitivity of the organism to growth-dependent antibiotics. From this it follows that, with more consistent and greater elevation of intragastric pH, more organisms are in the antibiotic-sensitive growth phase rather than the resistant stationary phase. Maintenance of an elevated pH for both day and night should put almost all H. pylori in growth phase. Therefore, the effect of profound acid inhibition on the bactericidal effect of amoxicillin will be tested in ivo in the gerbil. UreI, a proton-gated urea channel, forms an inner membrane complex at least with urease and the Ni2+ insertion subunits. Formation of this complex and interaction of other proteins that comprise the complex will be identified using state-of-the-art MS/MS techniques. The novel crystal structure of UreI will be used to identify the cytoplasmic loop binding sites of the proteins interacting with the channel. In the future, the loops identified as essential can be exploited for the development of novel and specific inhibitors of UreI complex formation. Successful completion of this aim could lead to an H. pylori-specific mono-therapy for eradication.

描述（由申请人提供）： 幽门螺杆菌感染了世界上一半人口的胃。这种感染是消化性溃疡病的主要原因，也是胃癌的高危因素。因此，根除幽门螺杆菌感染可以促进溃疡愈合并降低患胃癌的风险。在发现幽门螺杆菌之前，人们一直认为胃酸为细菌感染提供了一个不适宜的环境。然而，幽门螺杆菌独特地发展了在人胃的酸性表面上生存和生长的方法，这一过程被称为酸适应。破坏这个过程会导致在酸中失去生存能力；因此，这一过程的组成部分将为根除治疗提供新的目标。目前的根除疗法需要使用抗生素和酸抑制药物。由于抗生素耐药性增加，这些疗法的成功根除率正在下降，导致美国的缓解率约为 70%。 除非细菌处于生长期，否则生长依赖性抗生素克拉霉素或阿莫西林无效。改善酸抑制应该改善治疗效果。在第一个目标中，我们假设抑制酸分泌会增加生长期的细菌数量，使它们对生长依赖性抗生素敏感，因此除了抗生素外，还需要施用酸抑制化合物才能成功根除。研究发现，奥美拉唑缓慢代谢者单独使用奥美拉唑和阿莫西林可显着改善酸控制和有效根除，这表明改善的酸抑制可增加生物体对生长依赖性抗生素的敏感性。 由此可见，随着胃内 pH 值更加一致和更大的升高，更多的生物体处于抗生素敏感生长期而不是耐药静止期。白天和晚上保持较高的 pH 值将使几乎所有幽门螺杆菌都处于生长期。因此，将在沙鼠体内测试深度酸抑制对阿莫西林杀菌效果的影响。 UreI 是一种质子门控尿素通道，至少与尿素酶和 Ni2+ 插入亚基形成内膜复合物。该复合物的形成以及构成该复合物的其他蛋白质的相互作用将使用最先进的 MS/MS 技术进行鉴定。 UreI 的新型晶体结构将用于识别与通道相互作用的蛋白质的细胞质环结合位点。将来，被确定为必需的环可用于开发 UreI 复合物形成的新型特异性抑制剂。成功完成这一目标可能会导致幽门螺杆菌特异性单一疗法的根除。