Acid Adaptation Targets for Eradication of Helicobacter pylori

根除幽门螺杆菌的酸适应目标

• 批准号: 8242605
• 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 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242605
• 关键词: Acclimatization; Acidity; Acids; Amino Acids; Ammonia; Amoxicillin; Antibiotic Resistance; Antibiotics; Aspartate; Bacteria; Bacterial Infections; Bicarbonates; Binding; Buffers; Carbon Dioxide; Clarithromycin; Complex; Development; Down-Regulation; Drops; Enabling Factors; Ensure; Environment; Failure; Food; Gases; Gastric Juice; Gastric mucosa; Gene Cluster; Gene Targeting; Genes; Genetic Transcription; Gerbils; Glutamates; Grant; Growth; H(+)-K(+)-Exchanging ATPase; Healed; Helicobacter Infections; Helicobacter pylori; Histidine; Homology Modeling; Human; In Vitro; Infection; Investigation; Japan; Lead; Life Style; Maintenance; Measures; Medicine; Membrane; Methods; Metronidazole; Morbidity - disease rate; Mutation; Nature; Nutrient; Omeprazole; Organism; Outcome; Pathway interactions; Peptic Ulcer; Permeability; Pharmaceutical Preparations; Phase; Population; Process; Property; Protein Biosynthesis; Proteins; Regulation; Regulon; Relative (related person); Research; Resistance; Risk; Risk Factors; Role; Signal Transduction; Site; Site-Directed Mutagenesis; Small RNA; Stimulus; Stomach; Surface; System; Therapeutic; Time; Transcriptional Activation; Ulcer; United States; Up-Regulation; Urea; Urease; Veterans; base; carbonate dehydratase; cell growth; combat; drug development; extracellular; falls; healing; high risk; improved; in vivo; inhibitor/antagonist; malignant stomach neoplasm; membrane assembly; mortality; novel; pH Homeostasis; pathogen; periplasm; porin; prevent; promoter; protein-histidine kinase; protonation; public health relevance; response; sensor; success

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 this H. pylori infection leads to ulcer healing and lowers the risk of gastric cancer. Until 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 due to increasing antibiotic resistance, resulting in a response rate of < 80% in the USA. Acid acclimation is the ability of the organism to maintain a neutral periplasmic pH homeostasis in the presence of acid to allow gastric infection. Bacteria sense and respond to environmental stimuli via two component histidine kinase signaling systems. In the case of H. pylori, environmental acidification sensing is initiated through the HP0165/HP0166 two component system. Accordingly, the first hypothesis to be explored is that graded responses to acidity are regulated by this HP0165/HP0166 two component system. The system responds by acid-induced transcriptional upregulation of two promoters in the urease gene cluster, pureA and pureI, acid-induced post-translational upregulation of assembly UreI with apourease and the urease accessory proteins required for Ni2+ insertion along with Ni2+ entry, and also post-transcriptional down regulation by sRNAs at neutral pH. The UreI/urease membrane assembly is essential for acid acclimation and acid survival of the organism, and an understanding of the assembly mechanism is required for targeted therapy to this process. Therefore, the role of the HP0165/HP0166 TCS in membrane recruitment, assembly and activation of urease, in regulation of sRNA control of urease expression, and pH sensing by the TCS will be explored. 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 second 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 acid inhibition on the rate of H. pylori protein synthesis as an indicator of bacterial cell growth will be measured in vitro and in vivo. PUBLIC HEALTH RELEVANCE: H. pylori infection has a causal role in peptic ulcer disease and increases the risk of gastric cancer. Peptic ulcer disease and gastric cancer are major causes of morbidity in the Veterans population, in the United States and worldwide. H. pylori inhabits the stomach and has evolved unique acid response mechanisms to allow gastric colonization. Standard triple or quadruple therapies with acid blocking medicines and antibiotics have become less effective, falling below 80% success rate due to increasing antibiotic resistance. An understanding of how H. pylori colonizes the stomach will aid the development of novel eradication therapies. A possible strategy to replace current therapy is to target genes that allow the bacteria to survive in acid with non-antibiotic compounds. Another possible strategy is to improve control of the pH of the bacterial environment, so that dual therapy with acid inhibition and amoxicillin could be used. This would involve development of drugs with better acid blocking properties.

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，消除这种幽门螺杆菌感染会导致溃疡愈合并降低胃癌的风险。在发现幽门螺杆菌之前，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。该过程的破坏会导致酸中的生存损失，因此该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降低，导致美国的缓解率<80％。 酸的适应性是生物体在酸存在下保持中性周围pH稳态的能力，从而允许胃感染。细菌感和通过两个组分组氨酸激酶信号系统对环境刺激做出反应。在幽门螺杆菌的情况下，通过HP0165/HP0166两个组件系统启动环境酸化感应。因此，要探讨的第一个假设是对酸度的分级响应受此HP0165/HP0166的调节。该系统的反应是通过酸诱导的两个启动子在基因簇，PUREA和PUREI中的转录上调，酸诱导的与apourease组装的翻译后上调以及Ni2+插入所需的尿素辅助蛋白以及Ni2+入口以及Ni2+入口以及NI2+的尿布蛋白以及NI2+的入学后，以及在SRNAS中的转录下降。 UREI/尿素膜组件对于生物体的酸适应和酸存活至关重要，并且需要对靶向治疗进行此过程需要了解组装机制。因此，将探索HP0165/HP0166 TC在尿布募集，组装和激活中的作用，在调节尿素酶表达的SRNA控制方面以及TCS的pH感测。 除非细菌处于生长阶段，否则依赖于生长的抗生素克拉霉素或阿莫西林是无效的。改善酸抑制作用应改善治疗结果。在第二个目标中，我们假设抑制酸分泌增加了生长阶段中细菌的数量，使其对依赖生长的抗生素敏感，除了成功消除抗生素外，还需要对酸抑制性化合物进行施用。单独使用酸酸和阿莫西林的酸控制和有效根除的缓慢反应的发现，这一发现表明，改善的酸抑制作用会提高生物体对依赖生长抗生素的敏感性。因此，随之而来的是，随着胃内pH的更一致和更大的升高，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，将在体外和体内测量酸性抑制对细菌细胞生长的指标的影响。 公共卫生相关性： 幽门螺杆菌感染在消化性溃疡疾病中具有因果作用，并增加了胃癌的风险。消化性溃疡疾病和胃癌是美国和全球退伍军人人口发病率的主要原因。幽门螺杆菌居住在胃中，并发展了独特的酸反应机制以允许胃定植。用酸阻断药物和抗生素的标准三重或四倍疗法的有效性降低，由于抗生素耐药性的增加而降至80％的成功率。了解幽门螺杆菌如何殖民胃会有助于开发新的根除疗法。替代当前疗法的一种可能的策略是靶向基因，使细菌在非抗生素化合物中生存。另一个可能的策略是改善对细菌环境pH的控制，以便可以使用酸抑制和阿莫西林的双重治疗。这将涉及开发具有更好酸阻断特性的药物。