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

群体感应调节剂的小化学分子抑制剂的开发：抗生素耐药细菌感染的一种新治疗方法。

• 批准号: 10260554
• 负责人: Gopal P Jadhav
• 金额: $ 18.74万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260554
• 关键词: A549; Acetamides; Acetophenones; Achievement; Acquired Immunodeficiency Syndrome; Address; Agonist; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacterial Antibiotic Resistance; Bacterial Infections; Benzamides; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Burn injury; Cancer Patient; Cells; Cessation of life; Chemicals; Communication; Computer Models; Crystallization; Cystic Fibrosis; Data; Detection; Development; Docking; Dose; Drug Design; Drug Kinetics; Drug resistance; Exhibits; Family suidae; Generations; Germ; Goals; Gram-Negative Bacteria; Grant; Health; Histology; Hospitals; Human; Hydrophobicity; Immune; Immunocompromised Host; In Vitro; Incubated; Individual; Infection; Interdisciplinary Study; Intervention; Knowledge; Laboratories; Lead; Ligands; Lung; Lung infections; Microbial Antibiotic Resistance; Microbial Biofilms; Microbiology; Modeling; Nosocomial Infections; Pathogenicity; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Property; Proteins; Pseudomonas; Pseudomonas aeruginosa; Public Health; Pyocyanine; Regulon; Reporter; Reporting; Research Personnel; Research Proposals; Resistance; Resistance development; Roentgen Rays; Signaling Molecule; Solubility; Specificity; Structure; Structure of parenchyma of lung; Structure-Activity Relationship; Sulfones; Surface Plasmon Resonance; System; Technology; Testing; Therapeutic; Tissue Model; Tissues; Toxic effect; Treatment Efficacy; Virulence; Virulence Factors; Virulent; Work; analog; antibiotic tolerance; antimicrobial; aqueous; base; benzimidazole; clinically relevant; combat; cystic fibrosis patients; cytotoxicity; design; drug candidate; drug development; drug market; functional group; immunogenicity; improved; in vivo; inhibitor/antagonist; lead candidate; macrophage; mouse model; novel; novel strategies; novel therapeutics; opportunistic pathogen; pathogen; pharmacophore; phase 1 designs; preclinical development; preclinical evaluation; quorum sensing; research clinical testing; scaffold; side effect; small molecule inhibitor; tool

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.

抽象的： 小型化学分子抑制剂的开发群体传感调节剂：一种新的治疗方法 抗生素耐药细菌感染提交了R21：铜绿假单胞菌（PA），机会性病原体 对医院感染有重大健康威胁，特别是针对免疫功能低下的患者 烧伤，癌症和患有囊性纤维化或艾滋病的患者。 PA和其他病原体会产生抗生素耐药性 据报道，主要通过法定人数感应（QS）机制和每年> 23,000例死亡。解决 这个问题，最近发现分子（M64）靶向假单胞菌多种病毒因子 调节器（MVFR）。该药物在感染模型中经过验证的目标表现出严重的溶解度问题， 较少的暴露和诱变副作用。那迫切需要开发新的药物 这是针对MVFR目标的，这是当前研究建议的特定重点。 PA的MVFR QS系统 对于抗生素耐药性的发展至关重要。它控制着多种细菌病毒因子的表达 与致病性并引起对传统抗生素的耐药性有关的。我们的 MVFR-ligand（激动剂或拮抗剂）结合X射线结构中的药效学对接研究建议 这是药效对接和结构活动关系（SAR）将使新颖而有效的 MVFR抑制剂具有更好的药代动力学（PK）的抑制剂。以初步工作为基础 三个参与的实验室（Jadhav博士，Deziel博士和Diggle博士），我们将使用Pharmacopolore Docking， 以及基于结构的合理药物设计，以开发MVFR的小分子抑制剂。 MVFR一直在 使用M64和其他类似物在小鼠模型中被验证为抗菌靶 需要更好的PK来利用该目标的细节治疗潜力。在此R21赠款中，我们将设计 并使用具有的对接和SAR策略合成新颖的，结构相似和不同的抑制剂 成功地应用于Jadhav博士实验室中的相关目标。 SAR的化合物将评估 他们在HTS中以1 um的HTS活动进行化合生抑制作用，该抑制作用已在Dr. Deziel的实验室。然后，我们将优化体外生化，细胞，选择性药代动力学特性 开发铅化合物的抑制剂。铅化合物的功效将在EX中测试PA病毒 Diggle博士实验室开发的Vivo Pig Lung（EVPL）感染模型。这种多学科的合作 包括医学化学，计算和生物化学的必要综合专业知识， 药理学和微生物学。我们的长期目标是开发进一步的先进毒品候选人 临床前和临床评估是对抗抗生素抗生素铜绿假单胞菌和其他抗生素的新型抗生素 致病革兰氏阴性细菌。