Compounds to treat Helicobacter pylori infection

描述(由申请人提供)：该项目的目标是发现针对幽门螺杆菌的先导化合物，幽门螺杆菌是消化性溃疡和胃癌的病原体。大约所有其他人都携带这种病原体，据估计，美国每年有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的组合，通常是阿莫西林和克拉霉素。在一些患者中，耐药发生率增加，加上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，迫切需要新型抗菌剂来抗击这一重要疾病。然而，对革兰氏阴性菌起作用的最后一类抗生素--氟喹诺酮类--是50年前发现的。除了核心的基本基因组外，细菌还拥有数百个基本的、物种特有的基因。我们假设，如果我们不要求HITS具有广谱活性，这将为在传统化合物库中发现特定物种的抗菌素提供很高的可能性。对广谱化合物的共同关注是由于需要治疗原因不明的疾病。然而，消化性溃疡是由一种单一的病原体引起的，根据CDC的数据，美国治疗的市场估计超过60亿美元。幽门螺杆菌很挑剔，它的生长也不可靠。到目前为止，这阻碍了基于全细胞的HTS的发展，以识别具有直接抗病原体活性的化合物。我们的初步研究表明，已开发出一种可靠的抗幽门螺杆菌HTS。该屏幕确定了几个热门系列，这些系列经过有效性、新颖性、低细胞毒性和SAR验证，适合进一步开发。重要的是，这些化合物是幽门螺杆菌的特异性化合物，因为它们被一组肠道共生区反筛选，那些具有广泛活性的化合物被剔除。特异性抗H。幽门螺杆菌分子可能会击中人类没有的靶点，而且不会损害肠道菌群，避免了广谱抗生素的许多常见副作用，如恶心和腹泻。这为开发针对幽门螺杆菌的特定疗法提供了初步验证。在这个项目中，将根据四个经过验证的铅系列来生产定制合成库。化合物的详细体外验证将包括效力、活性光谱、抗药性发展、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力的明确的SAR，并确保随后的安全性和药代动力学优化是可以实现的。接下来，化合物将在幽门螺杆菌感染的小鼠模型中接受体内毒性、血清生物利用度和有效性的验证。对表现出动物功效的铅，将启动作用机制研究。第一阶段的最终结果将是在第二阶段开发的高级引线，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.