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一半人口的胃。这种感染是消化性溃疡疾病的主要原因，也是胃癌的高风险因素。因此，根除幽门螺杆菌感染会导致溃疡愈合并降低胃癌的风险。 UNIL发现幽门螺杆菌的发现，人们认为胃酸为细菌感染带来了一个荒凉的环境。然而，幽门螺杆菌已独特地开发了在人胃的酸性表面生存和生长的手段，这一过程称为酸的适应。这种过程的破坏会导致酸中的存活率丧失；因此，此过程的组成部分将为根除治疗提供新的目标。当前的根除疗法需要使用抗生素以及抑制酸性药物。由于抗生素耐药性的增加，这些疗法成功地消除了这些疗法的减少，导致美国的缓解率约为70％。 除非细菌处于生长阶段，否则生长依赖性抗生素克拉霉素或阿莫西林无效。改善酸抑制作用应改善治疗结果。在第一个目的中，我们假设抑制酸分泌会增加生长阶段的细菌数量，使其对生长依赖性抗生素敏感，除了成功地消除抗生素外，还需要对抗酸抑制性化合物进行施用。慢缓慢的奥美拉唑代谢剂仅通过大大改善的酸控制和单独使用奥司唑和阿莫西林的有效根除做出反应的发现表明，改善的酸抑制作用会提高生物体对生长依赖性抗生素的敏感性。 因此，随之而来的是，随着胃内pH的更加一致，更大的升高，更多的生物存在于抗生素敏感的生长阶段，而不是抗性固定阶段。昼夜维持升高的pH值应使几乎所有幽门螺杆菌都在生长阶段。因此，将在Gerbil的IVO中测试深度酸抑制对阿莫西林杀菌作用的影响。 UREI是一种质子门控尿素通道，至少在尿布和Ni2+插入亚基中形成内膜复合物。将使用最先进的MS/MS技术来识别这种复合物和其他蛋白质的相互作用的形成。 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，可以利用确定为必不可少的循环来开发UREI复合物形成的新颖和特定的抑制剂。成功完成此目标可能会导致幽门螺杆菌特异性的单疗法消除。