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

基本信息

批准号：
10641872
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
项目类别：
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/10641872
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 Combined Modality Therapy Data Disease Effectiveness Epithelium 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 Persons 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 burden of illness chronic infection design experimental study improved in vivo inhibitor innovation insight malignant stomach neoplasm metabolome mouse model mutant pathogen pathogenic bacteria synergism therapy development

项目摘要

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定义限制慢性病原体抗生素灵敏度的因素幽门螺杆菌。证据表明，慢性幽门螺杆菌很难用抗生素治愈，因为它在缓慢的生长状态至少部分由静止状态控制。幽门螺杆菌治疗依赖于通过内部去除酸甲状腺甲基强抗酸称为质子泵抑制剂（PPI）。 PPI阻止了酸的产生，升高 ACH pH，并促进幽门螺杆菌的生长。细菌生长使标准抗生素可以更好地工作。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差距，例如它的变量如何活跃 lism是酸是否是唯一的生长抑制剂，以及幽门螺杆菌在 PPI治疗。该信息很重要，因为在慢性状态下治疗了幽门螺杆菌感染。米尔全世界和美国的狮子都被幽门螺杆菌感染，并患有其相关疾病 - 溃疡和胃癌。胃癌是全球癌症死亡的第四个主要原因。幽门螺杆菌是随着事件在发达国家的稳定，持续的问题。此外，当前的疗法治疗幽门螺杆菌感染的频率不可接受：美国最近的估计发现 20-25％的感染者未通过当前的治疗方案治愈。这个ap-的总体目标应用是了解幽门螺杆菌慢性增长状态，并使用此信息来设计方法增强生长，从而增强抗生素灵敏度。我们的中心假设，基于已发表和初步的假设数据是，大多数慢性状态幽门螺杆菌处于极慢的生长模式，受A的限制酸，转化缺乏和营养限制的组合。在AIM 1中，我们将使用H的组合。幽门螺突变体和小鼠模型，以填补我们对幽门螺杆菌慢性生长态和增长率，这些参数如何受到PPI的影响，以及PPPI后乘法是否需要乳酸用作早期乘法的利用。此外，我们测试是否增加关键碳源裂缝可增强幽门螺杆菌慢性状态生长和抗生素治疗。在AIM 2中，我们以初步数据为基础显示幽门螺杆菌的生长缓慢显示出明显的翻译表达，包括通过增加核糖 - Mal沉默因子RSF。我们使用分子生物学和生物化学来填补我们对RSF的理解的空白一般的功能，并表征如何控制RSF的表达以及其他翻译抑制作用 TOR，控制翻译并影响慢性定殖。拟议的研究在其假设方面具有创新性幽门螺杆菌慢性缓慢的生长除了酸外还通过信号促进，并且知道和靶向这些将促进更好的治疗方法。拟议的研究很重要，因为它将为您提供新的见解慢性生长受到控制并提供了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结果将提供见解，为改进的基础奠定基础将这些微生物推入抗生素敏感态的疗法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Correction for Liu et al., "FliL Functions in Diverse Microbes to Negatively Modulate Motor Output via Its N-Terminal Region".

DOI：
10.1128/mbio.02396-23
发表时间：
2023-12-19
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

Altering under-represented DNA sequences elevates bacterial transformation efficiency.

DOI：
10.1128/mbio.02105-23
发表时间：
2023-12-19
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

Bacterial flagella hijack type IV pili proteins to control motility.

DOI：
10.1073/pnas.2317452121
发表时间：
2024-01-23
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Liu, Xiaolin;Tachiyama, Shoichi;Zhou, Xiaotian;Mathias, Rommel A.;Bonny, Sharmin Q.;Khan, Mohammad F.;Xin, Yue;Roujeinikova, Anna;Liu, Jun;Ottemann, Karen M.
通讯作者：
Ottemann, Karen M.

FliL Functions in Diverse Microbes to Negatively Modulate Motor Output via Its N-Terminal Region.