Narrow-spectrum Agents Acting against Helicobacter pylori

对抗幽门螺杆菌的窄谱药物

• 批准号: 8394159
• 负责人: Kenneth Coleman
• 金额: $ 29.75万
• 依托单位: ARIETIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394159
• 关键词: Accounting; Acids; Adverse effects; Amoxicillin; Animal Testing; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Back; Benchmarking; Binding; Biological Availability; Bismuth; Buffers; Chemicals; Clarithromycin; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Custom; Development; Diarrhea; Dose; Drug Delivery Systems; Drug Kinetics; Drug resistance; Evaluation; Exhibits; Failure; Fluoroquinolones; Frequencies; Goals; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; In Vitro; Incubated; Infection; Lead; Libraries; Mammalian Cell; Marketing; Measures; Meta-Analysis; Metabolic; Microbiology; Mus; Oral; Organism; Peptic Ulcer; Permeability; Persons; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Plasma; Problem Solving; Property; Protein Binding; Proteins; Proton Pump Inhibitors; Reflux; Regimen; Resistance; Resistance development; Rest; Safety; Sales; Screening procedure; Series; Site; Solubility; Species Specificity; Specificity; Staphylococcus aureus; Stomach; Stomach Carcinoma; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Treatment Failure; Triage; Ulcer; Validation; absorption; analog; animal efficacy; antimicrobial; base; counterscreen; cytotoxicity; design; efficacy testing; genome sequencing; improved; in vivo; innovation; iterative design; killings; lead series; malignant stomach neoplasm; member; mouse model; mutant; novel; novel therapeutics; pathogen; pre-clinical; resistant strain; therapeutic development

DESCRIPTION (provided by applicant): The goal of this project is to develop a therapeutic acting specifically against Helicobacter pylori, the causative agent of peptic ulcer and gastric carcinoma. Roughly every other person carries the pathogen, and there are an estimated 500,000 cases annually of active infection in the US. The currently-used triple therapy is a combination of a proton pump inhibitor and broad spectrum antimicrobials, usually amoxicillin and clarithromycin. A recent meta-analysis of clinical data showed that treatment failure is 22%. An estimated 70% of failures are due to antibiotic resistance. Considering the total number of cases, treatment failure is very high, and H. pylori is emerging as one of the most significant drug-resistant pathogens, and there is a considerable unmet need for novel treatments. The obstacles for discovering a new therapeutic are formidable - the last class of antibiotics acting against Gram negative species, the fluoroquinolones, was introduced 40 years ago. However, we reasoned that it should be considerably easier to develop a narrow-spectrum antimicrobial acting against H. pylori. Demands on a compound acting against a single target are less as compared to a broad- spectrum which needs to inhibit many proteins of an orthologous group. H. pylori also have a large number of unique essential proteins which could serve as targets for new antimicrobials. Poor permeability into Gram negative bacteria is another major obstacle for developing broad-spectrum compounds, but H. pylori do not have a strong permeability barrier. These considerations suggest that novel anti-H. Pylori compounds could be discovered in an HTS of commercial compounds libraries that failed to produce broad-spectrum antimicrobials. H. pylori grow under microaerophilic conditions, which are incompatible with standard HTS. We were able to develop a first HTS against H. pylori, and a pilot screen produced a large number of diverse hits. A major problem in HTS is a large number of toxic and promiscuous compounds. We solved this problem with a counter-screen against gut symbionts. This resulted in leads that are specific against H. pylori and will be free of side-effects such as diarrhea associated with broad-spectrum compounds that harm the gut flora. Validation of the hits resulted in a potent lead, 2MP, with an MIC and MBC of 0.04 ¿g/mL, low cytotoxicity, low resistance frequency, reasonable ADME, and an SAR, making it suitable for further development. The Phase I project will focus on closing SAR around the lead series, which will inform medicinal chemistry optimization in Phase II. Results from the pilot screen suggest that we have a validated discovery platform for selective anti-H. pylori compounds. We will take advantage of this, and will perform a larger HTS in order to identify a suitable back- up series. Iterative medicinal chemistry optimization will be combined with detailed validation of each series in Phase II. in vitro validation will include: potency, spectrum of activity, resistance development, acid stabilit, cytotoxicity, absorption, metabolic stability and plasma binding studies. Candidates suitable for animal testing will emerge from medicinal chemistry using iterative design-make-test cycles aimed at multifunctional optimization of the microbiological, pharmacologic and safety properties of each series. Next, compounds will undergo in vivo validation for suitable oral bioavailability and efficacy in a mouse model of H. pylori infection. Mechanism of action studies will be initiated for leads that exhibit animal efficacy. The end result will be validated leads that will enable us o enter into a partnership with a Pharmaceutical Company for further preclinical development leading towards and IND, clinical trials, marketing a sales of a new selective therapeutic for peptic ulcer. PUBLIC HEALTH RELEVANCE: The aim of this project is to identify compounds to treat Helicobacter pylori infection. H. pylori cause acid reflux, ulcers and stomach cancer. However, currently available therapeutics is broad spectrum antibiotics, which cause high levels of resistance and unwanted side-effects. We will develop an antibiotic that specifically targets H. pylori.

描述（由申请人提供）：本项目的目的是开发一种治疗药物，专门针对幽门螺杆菌，消化性溃疡和胃癌的病原体。大约每个人都携带病原体，美国每年估计有50万例活动性感染病例。目前使用的三联疗法是质子泵抑制剂和广谱抗菌药物的组合，通常是阿莫西林和克拉霉素。最近的一项临床数据荟萃分析显示，治疗失败率为22%。估计70%的失败是由于抗生素耐药性造成的。考虑到病例总数，治疗失败率很高，H。幽门螺杆菌正在成为最重要的耐药病原体之一，并且对于新的治疗存在相当大的未满足的需求。发现一种新的治疗方法的障碍是巨大的-最后一类针对革兰氏阴性菌的抗生素，氟喹诺酮类，是40年前引入的。然而，我们认为开发一种针对H.幽门。与需要抑制邻苯二甲酸酯基团的许多蛋白质的广谱化合物相比，对作用于单一靶标的化合物的需求较少。H.幽门螺杆菌还具有大量独特的必需蛋白质，这些蛋白质可以作为新的抗微生物剂的靶点。对革兰氏阴性菌的渗透性差是开发广谱化合物的另一个主要障碍，但H。pylori没有很强的渗透屏障。这些考虑表明，新的抗H。在未能产生广谱抗菌剂的商业化合物库的HTS中可以发现幽门螺杆菌化合物。H. pylori在微需氧条件下生长，这与标准HTS不相容。我们能够开发出第一个针对H的HTS。pylori，并且试验筛选产生了大量不同的命中。HTS的一个主要问题是大量的有毒和混杂的化合物。我们用一种对抗肠道共生菌的反屏障解决了这个问题。这导致了对H特异性的线索。幽门螺杆菌，并且将没有副作用，例如与损害肠道植物群的广谱化合物相关的腹泻。命中的验证产生了有效的先导化合物2 MP，其MIC和MBC为0.04 μ g/mL，细胞毒性低，耐药频率低，ADME合理，SAR，使其适合进一步开发。I期项目将重点关注电极导线系列的SAR，这将为II期药物化学优化提供信息。中试筛选的结果表明，我们有一个有效的选择性抗H的发现平台。幽门螺杆菌化合物。我们将利用这一点，并将执行一个更大的高温超导，以确定一个合适的备份系列。迭代药物化学优化将与II期每个系列的详细验证相结合。体外验证将包括：效价、活性谱、耐药性发展、酸稳定性、细胞毒性、吸收、代谢稳定性和血浆结合研究。适用于动物试验的候选药物将来自药物化学，使用迭代设计-制造-测试循环，旨在多功能优化每个系列的微生物学，药理学和安全性。接下来，化合物将在H小鼠模型中进行合适的口服生物利用度和功效的体内验证。幽门感染将启动作用机制研究 对动物有效的铅最终结果将是经过验证的线索，这将使我们能够与一家制药公司建立合作伙伴关系，进一步进行临床前开发，从而实现IND，临床试验，销售一种新的选择性治疗消化性溃疡的药物。 公共卫生相关性：该项目的目的是确定治疗幽门螺杆菌感染的化合物。H.幽门螺旋杆菌会导致胃酸倒流、溃疡和胃癌。然而，目前可用的治疗剂是广谱抗生素，其引起高水平的耐药性和不希望的副作用。我们将开发一种专门针对H.幽门。