Compounds to treat Helicobacter pylori infection

描述（由申请人提供）：该项目的目标是发现对幽门螺杆菌（消化性溃疡和胃癌的病原体）具有特异性作用的先导化合物。几乎每个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剂的组合，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。估计70%三联疗法失败的患者会产生抗生素耐药性。考虑到病例总数，治疗失败率非常高，迫切需要新型抗微生物药物来对抗这一重要疾病。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药物是在50年前发现的。除了核心的基本基因组外，细菌还拥有数百种基本的物种特异性基因。我们假设，如果我们不要求命中具有广谱活性，这将为在传统化合物文库中发现物种特异性抗菌剂提供很高的可能性。对广谱化合物的普遍关注是由于需要治疗病因不确定的疾病。然而，消化性溃疡是由单一病原体引起的，据疾病预防控制中心估计，美国的治疗市场超过60亿美元。幽门螺旋杆菌是挑剔的，它的生长是不可靠的。迄今为止，这阻碍了基于全细胞的HTS的发展，以鉴定对病原体具有直接活性的化合物。我们的初步研究表明，一种可靠的抗幽门螺旋杆菌HTS已经开发出来。筛选确定了几个热门系列，这些系列在效力、新颖性、低细胞毒性和SAR方面得到了验证，使它们适合进一步开发。重要的是，这些化合物对幽门螺杆菌是特异性的，因为它们对一组肠道共生体进行了反筛选，而那些具有广泛活性的化合物被淘汰了。具体anti-H。幽门螺杆菌分子可能会击中人类所没有的目标，并且不会伤害肠道菌群，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异性治疗方法提供了初步验证。在这个项目中，定制的合成库将基于四个经过验证的先导系列产生。化合物的详细体外验证将包括效力、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。这将确保观察到一个明确的效价SAR，并可实现随后的安全性和药代动力学优化。接下来，化合物将在幽门螺杆菌感染小鼠模型中进行体内毒性、血清生物利用度和有效性验证。将开始对表现出动物功效的铅的作用机制进行研究。第一阶段的最终结果将是在第二阶段开发的先进先导，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. PUBLIC HEALTH RELEVANCE: The aim of this Phase I project is to identify compounds to treat Helicobacter pylori infection. H. pylori causes acid reflux, ulcers and stomach cancer. However, currently available therapeutics are broad spectrum antibiotics, which cause high levels of resistance and unwanted side-effects. We will develop an antibiotic that specifically targets H. pylori.