Narrow-spectrum Agents Acting against Helicobacter pylori

对抗幽门螺杆菌的窄谱药物

• 批准号: 8692641
• 负责人: Kenneth Coleman
• 金额: $ 100万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692641
• 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; 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; screening; 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.

描述（由申请人提供）：该项目的目标是开发一种针对幽门螺杆菌（消化性溃疡和胃癌的病原体）的治疗药物。几乎每个人都携带这种病原体，据估计，美国每年有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剂的组合，通常是阿莫西林和克拉霉素。最近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。考虑到病例总数，治疗失败率非常高，并且幽门螺杆菌正在成为最重要的耐药病原体之一，并且对新治疗方法的需求仍未得到满足。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药物是在40年前引入的。然而，我们认为开发一种针对幽门螺杆菌的窄谱抗菌药物应该要容易得多。与需要抑制同源基团的许多蛋白质的广谱相比，对作用于单一靶标的化合物的要求较少。幽门螺杆菌还具有大量独特的必需蛋白，可作为新型抗菌剂的靶点。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，但幽门螺杆菌没有很强的渗透性屏障。这些考虑表明，新的反h。幽门螺杆菌化合物可以在商业化合物库的HTS中发现，这些化合物不能产生广谱抗菌剂。幽门螺杆菌在微嗜气条件下生长，这与标准HTS不相容。我们能够开发出第一个针对幽门螺杆菌的HTS，并且在试点筛选中产生了大量不同的成功。HTS的一个主要问题是大量有毒和混杂的化合物。我们用对抗肠道共生体的屏障解决了这个问题。这就产生了针对幽门螺杆菌的特异性药物，并且不会产生副作用，比如与损害肠道菌群的广谱化合物相关的腹泻。验证结果表明，有效的先导物为2MP， MIC和MBC为0.04¿g/mL，低细胞毒性，低耐药频率，合理的ADME和SAR，适合进一步开发。一期项目将重点围绕先导系列闭合SAR，这将为二期的药物化学优化提供信息。从试点筛选的结果表明，我们有一个有效的发现平台选择性抗h。螺杆菌的化合物。我们将利用这一点，并将执行一个更大的HTS，以确定一个合适的备份系列。迭代药物化学优化将与每个系列在II期的详细验证相结合。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、代谢稳定性和血浆结合研究。适合动物试验的候选药物将从药物化学中产生，使用迭代的设计-制造-测试周期，旨在对每个系列的微生物学，药理学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小鼠模型中进行适当的口服生物利用度和有效性的体内验证。将开始对行动机制进行研究