Molecular Archaeology: Vintage Beta Lactams for Resistant Gram Negative Infectio

描述(由申请人提供)：我们建议对现有的β-内酰胺类支架进行修改，以应对新出现的革兰氏阴性耐药威胁。从20世纪50年代到80年代，人们合成了大量的β-内酰胺类药物，但从未被开发成抗菌药物。在目前不断增加的耐药性的压力下，随着我们指尖积累了数十年的药物化学知识，其中某些分子重新引起了人们的兴趣，因为它们对后来进化出的耐药性机制不敏感。由于丝氨酸型(A类、C类和D类)和金属类(B类)β-内酰胺酶的传播，β-内酰胺类抗生素的使用受到了影响。碳青霉烯类对大多数A类和C类β-内酰胺酶稳定，但对B类酶和新兴的肺炎克雷伯菌碳青霉烯酶(KPC)A类酶敏感。相比之下，单内酰胺对B类金属酶本质上是稳定的，我们已经合成了一种对KPC酶额外稳定的原型化合物。一种对这些酶都不敏感的新试剂将对恢复β-内酰胺类的效用产生重大影响。我们已经评估了许多现有的、较老的β-内酰胺类药物，以对抗在β-内酰胺酶和外排泵方面表现良好的细菌小组。来自这个数据集的结构-活性关系(SAR)使我们能够设计几个新的β-内酰胺分子系列，这些分子有望保持对目前可用的药物具有抗药性的生物体的强大活性。我们假设我们可以修改一个精心挑选的支架，该支架对产生KPC酶的病原体具有活性，包括使其对A类和C类β-内酰胺酶有效的部分。为了实现这一目标，我们在项目的探索性R21阶段提出了两个目标，为我们提供候选药物。然后，我们提出了R33阶段的三个发展目标。R21阶段的目标包括：目标1.从光谱和效力方面优化所选先导化合物的体外活性。目的2.进行药物动力学(PK)研究，优化感染模型的疗效。在R33阶段进行的目标包括：目标3.进行更高级别的药代动力学研究。目的4.进行电池体外毒理学和中试毒理学研究。目的5.进行为期14天的射程毒理学研究。在这个项目成功完成后，我们将准备继续进行支持IND的毒理学研究。 与公共卫生相关：单胺类药物是一种类似青霉素的药物，过去用于治疗细菌性疾病。尽管它们的发展滞后于新的抗生素类别的出现，但对这些新类别的耐药性重新燃起了我们对单菌胺的兴趣。我们建议使用一种较老的单杆菌支架，并使用最近开发的化学物质对其进行修饰，以创建一种新型药物，该药物可以解决困难的、耐药的细菌感染。

DESCRIPTION (provided by applicant): We propose that existing beta-lactam scaffolds can be modified to address the emerging threat of Gram- negative resistance. A wealth of beta-lactams were synthesized from the 1950s into the 1980s but were never developed into antimicrobial drugs. Under the current stress of increasing drug resistance, and with decades of accrued medicinal chemistry knowledge at our fingertips, certain of these molecules are of renewed interest as a result of their non-susceptibility to resistance mechanisms that have since evolved. The utility of beta-lactam antibiotics has been compromised by the spread of beta-lactamase enzymes, both of the serine type (Classes A, C and D) and the metallo type (Class B). The carbapenems, while stable to most Class A and Class C beta-lactamases, are susceptible to Class B enzymes as well as emerging Klebsiella pneumoniae carbapenemase (KPC) Class A enzymes. Monobactams, by contrast, are intrinsically stable to Class B metalloenzymes, and we have synthesized a prototype compound that is additionally stable to KPC enzymes. A new agent that is not susceptible to any of these enzymes would have a major impact on restoring the utility of the beta-lactam class. We have evaluated numerous existing, older beta-lactam agents against panels of bacteria that are well-characterized with respect to expression of beta-lactamase enzymes as well as efflux pumps. The Structure-Activity Relationships (SAR) from this data set have enabled us to design several series of new beta-lactam molecules that are expected to retain potent activity against organisms that are resistant to currently-available agents. We hypothesize that we can modify a carefully selected scaffold that is active against pathogens producing KPC enzymes to include moieties that would make it potent against Class A and Class C beta-lactamases. To accomplish this, we propose two aims in the exploratory R21 phase of the project to provide us with our drug candidate. Then we propose three development aims in the R33 phase. The aims for the R21 phase include: Aim 1. Optimize the in vitro activity of the selected lead compounds with respect to spectrum and potency. Aim 2. Conduct pharmacokinetics (PK) studies and optimize efficacy in infection models. Aims to be conducted during R33 phase include: Aim 3. Conduct higher order pharmacokinetic studies. Aim 4. Conduct in vitro toxicology battery and pilot toxicology studies. Aim 5. Conduct 14-day range-finding toxicology studies. Upon successful completion of this project, we will be ready to proceed into IND-enabling toxicology studies. PUBLIC HEALTH RELEVANCE: Monobactams are penicillin-like drugs that were used to treat bacterial illness in the past. Though their development lagged with the advent of new classes of antibiotics, emerging drug-resistance to such newer classes has renewed our interest in monobactams. We propose to take an older monobactam scaffold and modify it using more recently developed chemistry to create a novel drug that can address difficult, drug-resistant bacterial infections.