Purine biosynthesis as a therapeutic target for Helicobacter pylori infection

嘌呤生物合成作为幽门螺杆菌感染的治疗靶点

• 批准号: 8385961
• 负责人: Joanna B Goldberg
• 金额: $ 8.88万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2013-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385961
• 关键词: Anabolism; Animals; Antibiotics; Antigens; Attenuated; Attenuated Vaccines; Bacteria; Carcinogens; Chronic; Cryptosporidiosis; Development; Drug Delivery Systems; Duodenal Ulcer; Enzymes; Gastric mucosa; Gastric ulcer; Genes; Goals; Growth; Helicobacter Infections; Helicobacter pylori; Human; IMP Dehydrogenase; Immune response; In Vitro; Infection; Inflammation; Life; Malignant Neoplasms; Mus; Mutate; Organism; Population; Proton Pump Inhibitors; Purines; Regimen; Research Project Grants; Resistance; Stomach; System; Testing; Toxic effect; Universities; Vaccination; Vaccines; antimicrobial; antimicrobial drug; attenuation; combat; compliance behavior; in vivo; inhibitor/antagonist; malignant stomach neoplasm; mouse model; mucosa-associated lymphoid tissue lymphoma; mutant; oral infection; pathogen; purine; research study; therapeutic target

DESCRIPTION (provided by applicant Helicobacter pylori is a Gram-negative, microaerophilic bacterium and one of the most common human bacterial pathogens, chronically infecting the gastric mucosa of approximately half of the world's population. While infection can be asymptomatic, H. pylori can cause chronic inflammation, duodenal and gastric ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. As the causative agent of human cancer, H. pylori is considered a class I carcinogen by the WHO. H. pylori infection persists throughout life unless the organism is eradicated. Antimicrobial therapies against H. pylori are available, but they require multidrug regimens in combination with proton-pump inhibitors, over the course of at least 7 days. In addition to problems with patient compliance, resistance to commonly used antibiotics is becoming an important problem. Thus, there is an urgent need for new antimicrobials to treat H. pylori. Even so, successful eradication via antimicrobial therapy does not protect against subsequent infection. Another approach to combat H. pylori is vaccination. The goal of the current Exploratory/Developmental Research Grant is to evaluate the enzyme inosine 5'- monophosphate dehydrogenase (IMPDH), involved in purine biosynthesis, as a viable drug target for H. pylori. We have already recognized compounds that can inhibit H. pylori IMPDH and the growth of H. pylori in vitro. Here we will evaluate newer compounds that display no toxicity at 250 mg/kg when given orally to mice and have been already been tested by our colleague Dr. Lizbeth Hedstrom (Brandeis University) in a mouse model of cryptosporidiosis. We will test these for growth inhibition of H. pylori in vitro and in a mouse model of H. pylori infection. We have also constructed an H. pylori strain with a deletion in the gene (guaB) that encodes IMPDH. We have shown that this mutant is auxotrophic and lacks IMPDH activity. Here, we will test whether the H. pylori ¿guaB mutant is attenuated in a mouse model of infection. Subsequently, it will be evaluated as a live vaccine to provide protection against H. pylori infection. If vaccination is effective, the mechanism of protection and protective antigens will be identified. If the ¿guaB mutant is not sufficiently attenuated other purine biosynthetic mutants with different auxotrophic requirements will be tested. The experiments in this proposal are the appropriate first steps to determine whether purine biosynthesis represents a viable therapeutic target for H. pylori. PUBLIC HEALTH RELEVANCE: Helicobacter pylori infect the stomach of 50% of the world's population; it can cause chronic inflammation, duodenal and gastric ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The goal of this Exploratory/Developmental Research Grant is to use mouse models of H. pylori infection to evaluate inhibitors of inosine 5'-monophosphate dehydrogenase (IMPDH) that are available from our collaborator Dr. Lizbeth Hedstrom (Brandeis University) as antimicrobial agents. Further, we will determine whether an H. pylori strain mutated in the gene encoding IMPDH can be used as a vaccine to protect against H. pylori infection.

描述（由申请人提供 幽门螺杆菌是一种革兰氏阴性、微需氧细菌，也是最常见的人类细菌病原体之一，慢性感染世界上大约一半人口的胃粘膜。虽然感染可能无症状，但幽门螺杆菌可导致慢性疾病炎症、十二指肠和胃溃疡、胃粘膜相关淋巴组织（MALT）淋巴瘤和胃癌。幽门螺杆菌是人类癌症的病原体，被世界卫生组织视为 I 类致癌物。 除非根除幽门螺杆菌，否则幽门螺杆菌感染将持续存在，但除了患者的问题外，还需要与质子泵抑制剂联合使用多种药物治疗。因此，迫切需要新的抗菌药物来治疗幽门螺杆菌，但通过抗菌治疗无法成功根除幽门螺杆菌。对抗幽门螺杆菌的另一种方法是接种疫苗。 当前探索性/发展研究补助金的目标是评估参与嘌呤生物合成的肌苷 5'-单磷酸脱氢酶 (IMPDH) 作为幽门螺杆菌的可行药物靶标。我们已经认识到可以抑制幽门螺杆菌的化合物。幽门螺杆菌 IMPDH 和幽门螺杆菌的体外生长在这里，我们将评估新的化合物，这些化合物在给小鼠口服 250 毫克/千克时没有表现出毒性，并且已经被研究过。我们的同事 Lizbeth Hedstrom 博士（布兰迪斯大学）在隐孢子虫病小鼠模型中进行了测试，我们将在体外和幽门螺杆菌感染小鼠模型中测试这些药物对幽门螺杆菌的生长抑制作用。编码 IMPDH 的基因 (guaB) 缺失的幽门螺杆菌菌株我们已经证明该突变体是营养缺陷型的并且缺乏 IMPDH 活性。在这里，我们将测试幽门螺杆菌是否存在。 ¿ guaB 突变体在小鼠感染模型中被减弱，随后将评估其作为活疫苗提供针对幽门螺杆菌感染的保护作用，如果疫苗接种有效，则将确定其保护机制和保护性抗原。 guaB 突变体未充分减弱，将测试具有不同营养缺陷型需求的其他嘌呤生物合成突变体。本提案中的实验是确定嘌呤生物合成是否代表幽门螺杆菌的可行治疗靶点的适当的第一步。 公众健康相关性：幽门螺杆菌感染世界上 50% 人口的胃；它可引起慢性炎症、十二指肠和胃溃疡、胃粘膜相关淋巴组织 (MALT) 淋巴瘤和胃癌。研究补助金将使用幽门螺杆菌感染的小鼠模型来评估肌苷 5'-单磷酸脱氢酶抑制剂(IMPDH)，可从我们的合作者 Lizbeth Hedstrom 博士（布兰迪斯大学）处获得作为抗菌剂。此外，我们将确定编码 IMPDH 的基因发生突变的幽门螺杆菌菌株是否可以用作预防幽门螺杆菌的疫苗。感染。