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（由适用提供）：该项目的目的是开发一种针对幽门螺杆菌的治疗作用，幽门螺杆菌是胡椒粉溃疡和胃癌的灾难性药物。大约每个其他人都具有病原体，在美国，每年估计有500,000例主动感染。当前使用的三重疗法是质子泵抑制剂和宽光谱抗菌药物（通常是阿莫西林和克拉霉素）的组合。最近对临床数据的荟萃分析表明，治疗失败为22％。估计由于抗生素耐药性，估计有70％的失败。考虑到病例的总数，治疗失败很高，幽门螺杆菌正在成为最重要的耐药病原体之一，并且考虑到新型治疗的需要考虑。发现一种新疗法的障碍是强大的 - 对革兰氏负物种作用氟喹诺酮类药物的最后类抗生素是40年前引入的。但是，我们应该更容易地开发针对幽门螺杆菌的狭窄曲线抗菌作用。与需要抑制直系同源群的许多蛋白质相比，对针对单个目标作用的化合物的需求较小。幽门螺杆菌也有大量独特的必需蛋白质，可以用作新的抗菌剂的靶标。革兰氏阴性细菌的渗透性差是发展广谱化合物的另一个主要障碍，但幽门螺杆菌没有强烈的渗透性屏障。这些考虑表明，新型抗H。幽门螺构化合物可以在未能产生广谱抗菌剂的商业化合物库中发现。幽门螺杆菌在微粒细胞条件下生长，与标准HTS不相容。我们能够针对幽门螺杆菌开发第一个HTS，而飞行员屏幕产生了大量潜水员的命中。 HTS中的一个主要问题是大量有毒和混杂的化合物。我们通过针对肠道符号的反屏幕解决了这个问题。这导致了针对幽门螺杆菌的特异性铅，并且将不含副作用，例如与伤害肠道菌群的宽光谱化合物相关的腹泻。验证点击的验证导致潜在的铅，2MP，MIC和MBC为0.04？g/ml，低细胞毒性，低电阻频率，合理的ADD和SAR，使其适合进一步发展。第一阶段项目将着重于关闭铅系列的SAR，这将为II阶段的医学化学优化提供信息。试点屏幕的结果表明，我们有一个验证的选择性抗H的发现平台。幽门螺构化合物。我们将利用这一点，并将执行更大的HTS以确定合适的备份系列。迭代医学化学优化将与第二阶段中每个系列的详细验证相结合。体外验证将包括：效力，活性谱，耐药性发展，酸稳定性，细胞毒性，吸收性，代谢稳定性和血浆结合研究。适合动物测试的候选物将使用迭代设计策略周期从医学化学中出现，该周期旨在对每个系列的微生物，药理和安全性进行多功能优化。接下来，化合物将在幽门螺杆菌感染的小鼠模型中进行适当的口服生物利用度和效率的体内验证。行动研究机理将开始 对于暴露动物效率的潜在客户。最终结果将得到验证的潜在客户，这将使我们能够与制药公司建立合作伙伴关系，以进一步促进临床前开发和IND，临床试验，营销针对胡椒粉溃疡的新选择疗法的销售。 公共卫生相关性：该项目的目的是识别治疗幽门螺杆菌感染的化合物。幽门螺杆菌会导致酸反射，溃疡和stallch癌。但是，目前可用的治疗是广谱抗生素，它会引起高水平的耐药性和不必要的副作用。我们将开发一种专门针对幽门螺杆菌的抗生素。