Medicinal Chemistry

细菌的通讯、耐药性和毒力机制仍然是小规模杀伤性武器的代表性不足的目标。 分子药物化学抗微生物药物发现的相对狭窄的焦点是 在革兰氏阴性感染领域尤其急性，这一类包括与以下相关的病原体： 潜在的生物恐怖主义行为（鼠疫耶尔森氏菌、类鼻疽伯克霍尔德氏菌）、新出现的感染（大肠杆菌 co//O157：H7）和持续性感染（铜绿假单胞菌）。有令人信服的理由 了解毒力机制，并使用小分子化学来做到这一点。药物针对 毒力靶标不太可能在细菌中引起抗性应答。新型药物和药物 针对新靶点，也不太可能被预先存在的耐药机制所偏转， 细菌鉴于此，我们正在开发针对新毒力靶点的新化合物， 潜在的治疗和作为微生物学研究工具。在这份提案中，我们概述了我们的进展和计划 使用化学生物学/药物化学来理解并最终操纵两种与药物相关的药物， 系统、III型分泌（T3SS）和双-（3'-5'）环二胍酸（c-di-GMP）信号传导。为 项目，目标是合成分子，将（a）使理解的分子细节， 这些复杂的低聚物系统的动力学和结构，（B）以验证这些系统中的靶标， 用于药物发现的系统，以及（c）产生用于开发人类治疗剂的主要候选物 瞄准这些系统。在T3SS项目中，我们合成了我们最初的高通量的衍生物。 筛选命中（TTSS 29），不仅提高其活性10倍和100倍，而且提高了 这种化学类型是一种现实的治疗方法。当考虑到沿着与早期购买的化合物， 我们的新型合成化合物小组现已超过50个，为我们进一步开发 TTSS 29所属的2-亚氨基噻唑烷酮类的改进。在c-di-GMP项目中， 合成了一类新的已知信号分子的稳定类似物（即c-di-GMP本身）和几种 无环二聚体的开环-二-GMP类似物，pGpG，一种可能具有尚未报道的信号传导的分子 自己的财产。目前，没有c-di-GMP的小分子抑制剂、激动剂或拮抗剂， 路径已被报道。我们将评估我们的新型c-di-GMP和s-di-GMP类似物作为以下抑制剂： 上调环化酶、下调磷酸二酯酶，以及作为已知CDI-的激动剂/拮抗剂， GMP介导的反应。根据这些数据，以及我们在本文中描述的计算机屏幕，我们将 创造新的化合物，旨在验证并最终利用c-di-GMP信号传导作为治疗药物， 革兰氏阴性菌感染靶点。

Bacterial communication, resistance, and virulence mechanisms remain underrepresented targets for small molecule-based medicinal chemistry. The relatively narrow focus of antimicrobial drug discovery is particularly acute in the area of Gram-negative infections, a class that includes pathogens relevant to potential acts of bioterrorism (Yersinia pestis, Burkholderia pseudomalleii), emerging infections (Escherichia co// O157:H7), and persistent infections (Pseudomonas aeruginsoa). There are compelling reasons to understand virulence mechanisms, and to use small molecule chemistry to do so. Drugs directed at virulence targets are less likely to provoke a resistance response in the bacteria. Novel drugs, and drugs directed at novel targets, are also less likely to be deflected by pre-existing drug resistance mechanisms in the bacteria. In light of this, we are developing novel compounds directed at novel virulence targets as potential therapeutics and as microbiology research tools. In this proposal we outline our progress and plans using chemical biology/medicinal chemistry to understand and ultimately manipulate two virulence-related systems, type III secretion (T3SS) and bis-(3'-5') cyclic diguanilic acid (c-di-GMP) signaling. For both projects, the goals are to synthesize molecules that will (a) enable understanding the molecular details of the dynamics and architechture of these complex oligomeric systems,(b) to validate targets within these systems for drug discovery, and (c) to produce lead candidates for development as human therapeutics targeting these systems. In the T3SS project we have synthesized derivatives of our original high-throughput screen hit (TTSS29) that not only improve upon its activity 10 and 100-fold but also improve the potential of this chemotype to be a realistic therapeutic. When considered along with the earlier purchased compounds, our panel of novel synthetic compounds¿now over 50- provide the guidance we need for further refinements in the 2-iminothiazolidinone class to which TTSS29 belongs. In the c-di-GMP project, we have synthesized a novel class stable analogs of the known signaling molecule (i.e. c-di-GMP itself) and several seco-di-GMP analogs of the acyclic dimer, pGpG, a molecule that may have as-yet-unreported signaling properties of its own. Currently, no small molecule inhibitors, agonists, or antagonists of the c-di-GMP pathway have been reported. We will evaluate our novel c-di-GMP and s-di-GMP analogs as inhibitors of the upregulating cyclase, the downregulating phosphodiesterase, and as agonists /antagonists of known cdi- GMP mediated responses. From these data, and from an in silico screen we describe herein, we will create new compounds intended to validate, and ultimately exploit, c-di-GMP signalling as a therapeutic target in Gram-negative infections .