Medicinal Chemistry

细菌通讯、耐药性和毒力机制仍然是小病毒的目标 基于分子的药物化学。抗菌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严重，这类感染包括与 潜在的生物恐怖主义行为(鼠疫耶尔森氏菌、假鼻疽伯克霍尔德氏菌)、新出现的感染(埃希里希菌 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。针对以下目标的毒品 毒力靶标不太可能在细菌中引发耐药性反应。新药，和药物 针对新的靶点，也不太可能被先前存在的耐药性机制所转移 细菌。有鉴于此，我们正在开发针对新的毒力靶点的新化合物，如 潜在的治疗方法和微生物学研究工具。在这份提案中，我们概述了我们的进展和计划 利用化学生物学/药物化学来理解并最终操纵两种与毒力相关的 系统、III型分泌物(T3SS)和双-(3‘-5’)环二鸟苷酸(c-di-GMP)信号系统。对两个人都是 项目，目标是合成分子，将(A)使理解分子细节 这些复杂低聚体系的动力学和体系结构，(B)验证这些体系中的靶标 药物发现系统，以及(C)产生作为人类治疗学开发的主要候选者 瞄准这些系统。在T3SS项目中，我们已经合成了我们最初的高通量的衍生产品 屏幕点击(TTSS29)，不仅其活跃度提高10倍和100倍，而且还提高了 这种化学类型是一种现实的治疗方法。当与早先购买的化合物一起考虑时， 我们的新型合成化合物小组？现在超过50种-提供我们需要的指导，以进一步 TTSS29所属的2-亚氨基噻唑烷酮类化合物的精制。在c-di-GMP项目中，我们有 合成了一类新的稳定的已知信号分子类似物(即c-di-GMP本身)和几个 Seco-di-GMP类似物，非环二聚体，pGpG，一种可能具有尚未报道的信号的分子 它自己的属性。目前，还没有c-di-GMP的小分子抑制剂、激动剂或拮抗剂。 其途径已有报道。我们将评估我们的新型c-di-GMP和S-di-GMP类似物作为血管紧张素转换酶抑制剂 上调的循环酶，下调的磷酸二酯酶，以及作为已知CDI的激动剂/拮抗剂- GMP介导的反应。从这些数据以及我们在此描述的In Silo屏幕，我们将 创造新的化合物，旨在验证并最终利用c-di-GMP信号作为一种治疗 以革兰氏阴性感染为目标。

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 .