Development of small chemical-molecule inhibitors of quorum sensing regulator: a novel treatment for antibiotic resistant bacterial infections.

摘要： 群体感应调节剂小分子抑制剂的开发：一种新的治疗方法 为R21提交的耐抗生素细菌感染：铜绿假单胞菌(PA)，条件致病菌 是对医院感染的重大健康威胁，特别是对免疫功能低下的患者 烧伤、癌症、囊性纤维症或艾滋病患者。PA和其他病原体对抗生素产生抗药性 主要是通过群体感应(QS)机制，据报道每年有23,000人死亡。致信地址 这个问题是最近发现的针对假单胞菌多重毒力因子的分子(M64) 调节器(MvfR)。在感染模型中这个药物验证的靶点表现出严重的溶解性问题， 较少的暴露和诱变副作用。因此，迫切需要开发新的药物 这解决了MvfR目标，这是当前研究提案的一个具体重点。页面的MvfR QS系统 对抗生素耐药性的发展起着关键作用。它控制着多种细菌毒力因子的表达。 它们与致病性有关，并引起对传统抗生素的耐药性。我们的 MvfR配体(激动剂或拮抗剂)结合的X射线结构中的药效团对接研究 因此，药效团的对接和构效关系(SAR)将使开发新的和有效的 MvfR抑制剂的药代动力学(PK)好于现有的抑制剂。基于以下项目的前期工作 三个参与实验室(贾达夫博士、德齐尔博士和迪格尔博士)，我们将使用，药效团对接， 以及基于结构的合理药物设计，开发MvfR小分子抑制剂。MvfR一直是 在使用M64和其他类似物的小鼠模型中验证为抗菌靶点，但更有效的药物是 需要更好的PK来开发这一靶点的详细治疗潜力。在这笔R21拨款中，我们将设计 并使用对接和SAR策略合成新的、结构相似和不相似的抑制剂 已成功应用于贾达夫博士实验室的相关目标。将对来自SAR的化合物进行评估 对于它们在HTS中的活性，1微米的单次剂量对绿青素的抑制已经在DR 德齐尔的实验室。然后我们将优化其体外生化、细胞、选择性药代动力学特性。 开发先导化合物的抑制剂。先导化合物的效力将在EX中进行PA毒力测试 Digger博士实验室建立的活体猪肺(EVPL)感染模型这种多学科协作 包括药物化学、计算和生物化学方面的必要综合专业知识， 药理学和微生物学。我们的长期目标是进一步开发先进的候选药物 作为对抗耐药铜绿假单胞菌等新型抗生素的临床前和临床评价 致病的革兰氏阴性菌。

Abstract: Development of small chemical-molecule inhibitors of quorum sensing regulator: a novel treatment for antibiotic resistant bacterial infections submitted for R21: P. aeruginosa (Pa), opportunistic pathogens that are substantial health threat to nosocomial infections, especially for immunocompromised patients with burns, cancer, and patients with cystic fibrosis or AIDS. Pa and other pathogens develop antibiotic resistance mainly through quorum sensing (QS) mechanism and >23,000 deaths per annum are reported. To address this problem, recently molecule (M64) was discovered that target the Pseudomonas multiple virulence factor regulator (MvfR). This pharmacologically validated target in infection models exhibits serious solubility issues, less exposure and mutagenic side effects. Thus, there is an urgent need for the development of novel drugs that addresses MvfR target, and this is a specific focus of current research proposal. MvfR QS system of Pa is pivotal for development of antibiotic resistant. It controls expression of a variety of bacterial virulence factors that are associated with pathogenicity and to elicit drug resistance to traditional antibiotics. Our pharmacophore docking studies in MvfR-ligand (agonist or antagonist) bound X-ray structures suggested that, pharmacophore docking and structure activity relationship (SAR) will enable to develop novel and potent MvfR inhibitors with better pharmacokinetic (PK) than current inhibitors. Building upon preliminary work from three participating laboratories (Dr. Jadhav, Dr. Deziel and Dr. Diggle), we will use, pharmacophore docking, and structure-based rational drug design to develop small molecule inhibitors of MvfR. MvfR has been validated as antibacterial target in a mouse model using M64 and other analogues, but more potent drug with better PK are required to exploit detail therapeutic potential of this target. In this R21 grant, we will design and synthesize novel, structurally similar and dissimilar inhibitors using a docking and SAR strategy that has been applied successfully to related targets in the Dr. Jadhav’s lab. Compounds from SAR will be evaluated for their activities in HTS at single dose of 1 uM for pyocyanin inhibition that has been established in the Dr. Deziel’s lab. We will then optimize the in vitro biochemical, cellular, selective pharmacokinetic properties of the inhibitors to develop lead compounds. Efficacy of lead compounds will be tested for Pa virulence in ex vivo Pig Lung (EVPL) infection model developed by Dr. Diggle’s Lab. This multidisciplinary collaboration comprises the necessary combined expertise in medicinal chemistry, computational and biochemistry, pharmacology, and microbiology. Our long- term goals are to develop advanced drug candidates for further preclinical and clinical evaluations as novel antibiotics to combat antibiotic resistant P. aeruginosa and other pathogenic Gram-negative bacteria.