Molecular Archaeology: Vintage Beta Lactams for Resistant Gram Negative Infectio

描述（由申请人提供）：我们提出可以对现有的β-内酰胺支架进行修饰，以解决革兰氏阴性耐药的新威胁。从20世纪50年代到80年代，合成了大量的β-内酰胺，但从未开发成抗菌药物。在当前耐药性增加的压力下，并且随着数十年来积累的药物化学知识在我们的指尖，这些分子中的某些分子由于其对已经进化的耐药机制的不敏感性而重新引起人们的兴趣。β-内酰胺类抗生素的效用已受到丝氨酸型（A类、C类和D类）和金属型（B类）β-内酰胺酶传播的影响。碳青霉烯类虽然对大多数A类和C类β-内酰胺酶稳定，但对B类酶以及新出现的肺炎克雷伯菌碳青霉烯酶（KPC）A类酶敏感。相比之下，单环内酰胺对B类金属酶本质上是稳定的，并且我们已经合成了对KPC酶另外稳定的原型化合物。一种对这些酶中的任何一种都不敏感的新药物将对恢复β-内酰胺类药物的效用产生重大影响。我们已经评估了许多现有的、较旧的β-内酰胺类药物对细菌组的作用，这些细菌组在β-内酰胺酶的表达以及外排泵方面具有良好的特征。来自该数据集的结构-活性关系（SAR）使我们能够设计几个系列的新β-内酰胺分子，这些分子预计将保留针对对当前可用药剂具有抗性的生物体的有效活性。我们假设，我们可以修改一个精心选择的支架，是积极的病原体产生KPC酶，包括部分，使其有效的A类和C类β-内酰胺酶。为了实现这一目标，我们在该项目的探索性R21阶段提出了两个目标，为我们提供候选药物。在此基础上，提出了R33阶段的三个发展目标。R21阶段的目标包括：目标1。优化所选先导化合物在光谱和效价方面的体外活性。目标2.在感染模型中进行药代动力学（PK）研究并优化疗效。在R33阶段将实现的目标包括：目标3。进行高阶药代动力学研究。目标4。进行体外毒理学组合和初步毒理学研究。目标5。进行14天剂量范围探索毒理学研究。成功完成该项目后，我们将准备进行IND毒理学研究。

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.