Compounds to treat Helicobacter pylori infection

描述（由申请人提供）：本项目的目标是发现特异性对抗幽门螺杆菌（消化性溃疡和胃癌的病原体）的先导化合物。大约每个人都携带病原体，美国每年估计有150万例活动性感染病例。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。耐药的发生率增加，加上一些患者对该方案的耐受性差，导致15-25%的治疗失败。据估计，三联疗法失败的患者中有70%会产生抗生素耐药性。考虑到病例总数，治疗失败率非常高，迫切需要新型抗菌药物来对抗这一重要疾病。然而，最后一类针对革兰氏阴性菌的抗生素氟喹诺酮类是50年前发现的。 除了核心的必需基因组，细菌还拥有数百个必需的物种特异性基因。我们假设，这将提供一个很高的可能性，在传统的化合物库中发现物种特异性抗菌剂，如果我们不需要命中具有广谱活性。对广谱化合物的共同关注取决于治疗病因不确定的疾病的需要。然而，消化性溃疡是由单一病原体引起的，据CDC估计，美国治疗市场超过60亿美元。 H. pylori是挑剔的，并且它的生长是不可靠的。这阻碍了基于全细胞的HTS的开发，以鉴定具有针对病原体的直接活性的化合物，直到现在。我们的初步研究表明，一个可靠的高温超导抗H。pylori已经发展起来了。筛选鉴定了几个命中系列，这些命中系列的效力、新奇、低细胞毒性和SAR得到了验证，使其适合进一步开发。重要的是，这些化合物对H是特异性的。pylori，因为它们是针对一组肠毒素进行反筛选的，并且具有广泛活性的那些被排除。特异性抗H.幽门螺杆菌分子可能击中了人类没有的目标，不会损害肠道植物群，避免了广谱抗生素的许多常见副作用，如恶心和腹泻。这为开发针对H.幽门。 在本项目中，将基于四个经验证的先导化合物系列生产定制合成文库。化合物的详细体外验证将包括效价、活性谱、耐药性发展、细胞毒性、吸收、代谢稳定性和血浆结合研究。这将确保观察到关于效价的明确SAR，并且可实现随后的安全性和药代动力学优化。接下来，化合物将在H.幽门感染将对表现出动物疗效的电极导线启动作用机制研究。第一阶段的最终结果将是在第二阶段开发的高级电极导线，从而产生IND。

DESCRIPTION (provided by applicant): The goal of this project is to discover lead compounds 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 1.5 million 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. Increased incidence of resistance combined with poor tolerance of the regimen in some patients results in 15-25% of treatment failure. An estimated 70% of patients who fail triple therapy develop antibiotic resistance. Considering the total number of cases, treatment failure is very high, and there is an urgent need for novel classes of antimicrobials to combat this important disease. However, the last class of antibiotics acting against Gram negative species, the fluoroquinolones, was discovered 50 years ago. Apart from the core essential genome, bacteria possess hundreds of essential, species-specific genes. We hypothesize that this will provide a high likelihood for discovering species-specific antimicrobials in a conventional compound library, if we do not require hits to have broad-spectrum activity. The common focus on broad-spectrum compounds is dictated by the need to treat diseases with uncertain causes. However, peptic ulcer is caused by a single pathogen and the estimated US market for treatment is over 6 billion dollars according to the CDC. H. pylori is fastidious, and its growth is unreliable. This has prevented the development of a whole cell based HTS to identify compounds with direct activity against the pathogen until now. Our preliminary studies show that a reliable HTS against H. pylori has been developed. The screen identified several hit series which were validated for potency, novelty, low cytotoxicity and SAR, making them suitable for further development. Importantly, these compounds are specific for H. pylori since they were counter-screened against a panel of gut commensals and those with broad activity were eliminated. Specific anti-H. pylori molecules likely hit a target absent in humans, and will not harm the intestinal flora, avoiding many of the common side effects of broad spectrum antibiotics such as nausea and diarrhea. This provides preliminary validation for the approach to develop specific therapeutics targeting H. pylori. In this project, custom synthetic libraries will be produced based on four validated lead series. Detailed in vitro validation of compounds will include potency, spectrum of activity, resistance development, cytotoxicity, absorption, metabolic stability and plasma binding studies. This will ensure that a clear SAR with respect to potency is observed and that subsequent optimization for safety and pharmacokinetics is attainable. Next, compounds will undergo in vivo validation for toxicity, blood serum 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 of Phase I will be advanced leads that will be developed in Phase II, resulting in an IND.