Understanding and manipulating chronic Helicobacter pylori to enhance treatment

了解和控制慢性幽门螺杆菌以加强治疗

• 批准号: 10316849
• 负责人: Karen M Ottemann
• 金额: $ 37.76万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316849
• 关键词: Acids; Adopted; Affect; Amoxicillin; Antacids; Antibiotics; Bacteria; Behavior; Biochemistry; Cancer Etiology; Carbon; Cessation of life; Chronic; Chronic Phase; Clarithromycin; Colony-forming units; Data; Disease; Effectiveness; Epithelial; Frequencies; Gastric ulcer; Gene Proteins; Genetic Transcription; Gland; Green Fluorescent Proteins; Growth; Growth Inhibitors; Health; Helicobacter Infections; Helicobacter pylori; Human; Incidence; Individual; Infection; Knowledge; Measurement; Measures; Metabolism; Microbe; Mission; Molecular Biology; Mus; Mycobacterium tuberculosis; Nature; Neisseria; Nutrient; Organism; Outcome; Panthera leo; Physiology; Population; Population Sizes; Production; Proteins; Proton Pump Inhibitors; Public Health; Publishing; Refractory; Research; Ribosomal Proteins; Ribosomes; Rodent Model; Scheme; Signal Transduction; Solid; Source; Stomach; Testing; Therapeutic; Time; Translational Repression; Translations; Treatment Effectiveness; Ulcer; United States; United States National Institutes of Health; Work; base; burden of illness; chronic infection; design; experimental study; improved; in vivo; inhibitor/antagonist; innovation; insight; malignant stomach neoplasm; metabolome; mouse model; mutant; mutant mouse model; pathogen; pathogenic bacteria; therapy development

Our proposed research focuses on defining factors that limit antibiotic sensitivity of the chronic pathogen Heli- cobacter pylori. Evidence suggests that chronic H. pylori is difficult to cure with antibiotics because it is in a slow growth state controlled at least in part by stomach acid. H. pylori treatments rely on removing acid by in- cluding strong antacids called proton pump inhibitors (PPI). The PPI blocks acid production, raises the stom- ach pH, and promotes H. pylori growth. Bacterial growth allows standard antibiotics to work better. There is a gap in our understanding of the exact nature of the H. pylori chronic growth state, e.g. how active its metabo- lism is, whether acid is the only growth inhibitor, and what type of metabolism H. pylori deploys to grow after PPI treatment. This information is important because H. pylori infections are treated at the chronic state. Mil- lions of people worldwide and in the U.S. are infected by H. pylori and suffer from its associated diseases— ulcers and gastric cancer. Gastric cancer is the fourth leading cause of cancer deaths worldwide. H. pylori is an on-going problem, as the incidence has stabilized in the developed world. Furthermore, current therapies to cure H. pylori infection fail with unacceptable frequency: recent estimates in the United States have found that 20-25% of infected individuals are not cured by the current therapeutic regime. The overall objective of this ap- plication is to understand the H. pylori chronic growth state and use this information to design approaches that enhance growth and therefore antibiotic sensitivity. Our central hypothesis, based on published and preliminary data, is that the majority of chronic-state H. pylori are in an extreme slow growth mode, limited by a combination of acid, translational deficiency, and nutrient restriction. In Aim 1, we will use a combination of H. pylori mutants and mouse models to fill gaps in our understanding of the H. pylori chronic growth state and growth rate, how these parameters are affected by PPI, and whether post-PPI multiplication requires lactate utilization as early stage multiplication does. Additionally, we test whether increasing key carbon sources like lactate enhances H. pylori chronic state growth and antibiotic cure. In Aim 2, we build on preliminary data showing slow growth H. pylori display significant translational repression, including by increase in the riboso- mal silencing factor RsfS. We use molecular biology and biochemistry to fill gaps in our understanding of RsfS function in general, and to characterize how controlled RsfS expression, as well as other translational inhibi- tors, controls translation and affect chronic colonization. The proposed research is innovative in its hypothesis that H. pylori chronic slow growth is promoted by signals in addition to acid, and that knowing and targeting these will promote better cures. The proposed research is significant because it will provide new insights into ways that chronic growth is controlled and provide new ways to enhances H. pylori antibiotic sensitivity. The long-term outcomes generated by this research will provide insights that will lay the groundwork for improved therapies that push these microbes into an antibiotic-sensitive state.

我们提出的研究重点是限制慢性病原体Heli-抗生素敏感性的定义因素 幽门螺杆菌。有证据表明，慢性幽门螺杆菌很难用抗生素治愈，因为它处于一种 缓慢的生长状态至少部分由胃酸控制。幽门螺杆菌治疗依赖于通过体内去除酸 包括称为质子泵抑制剂（PPI）的强抗酸剂。 PPI 阻止酸的产生，提高 stom- 改变 pH 值，并促进幽门螺杆菌生长。细菌生长使标准抗生素发挥更好的作用。有一个 我们对幽门螺杆菌慢性生长状态的确切性质的理解存在差距，例如它的代谢有多活跃 其要点是，酸是否是唯一的生长抑制剂，以及幽门螺杆菌在生长后采用什么类型的代谢来生长。 PPI治疗。该信息很重要，因为幽门螺杆菌感染是在慢性状态下进行治疗的。军用 世界各地和美国有大量的人感染了幽门螺杆菌并患有其相关疾病—— 溃疡和胃癌。胃癌是全球第四大癌症死亡原因。幽门螺杆菌是 随着发达国家的发病率稳定下来，这一问题正在持续存在。此外，目前的治疗方法 治愈幽门螺杆菌感染失败的频率令人无法接受：美国最近的估计发现， 目前的治疗方案无法治愈 20-25% 的感染者。该应用程序的总体目标 复制的目的是了解幽门螺杆菌的慢性生长状态，并利用这些信息来设计方法 促进生长，从而提高抗生素敏感性。我们的中心假设基于已发表的和初步的 数据显示，大多数慢性状态幽门螺杆菌处于极其缓慢的生长模式，受限于 酸、翻译缺陷和营养限制的结合。在目标 1 中，我们将使用 H. 幽门螺杆菌突变体和小鼠模型填补了我们对幽门螺杆菌慢性生长状态理解的空白 生长速率、这些参数如何受 PPI 影响，以及 PPI 倍增后是否需要乳酸 像早期乘法一样利用。此外，我们测试是否增加关键碳源，例如 乳酸可促进幽门螺杆菌慢性生长和抗生素治愈。在目标 2 中，我们以初步数据为基础 显示生长缓慢 幽门螺杆菌表现出显着的翻译抑制，包括核糖体的增加 恶意沉默因子RsfS。我们利用分子生物学和生物化学来填补我们对 RsfS 理解的空白 一般功能，并表征如何控制 RsfS 表达，以及其他翻译抑制 器，控制翻译并影响长期定植。拟议的研究在假设上具有创新性 除酸外，信号还促进幽门螺杆菌慢性缓慢生长，并且了解和靶向 这些将促进更好的治疗。拟议的研究意义重大，因为它将提供新的见解 控制慢性生长的方法并提供增强幽门螺杆菌抗生素敏感性的新方法。这 这项研究产生的长期成果将提供见解，为改进奠定基础 将这些微生物推入抗生素敏感状态的疗法。