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.

摘要： 群体感应调节因子小分子抑制剂的开发：一种新的治疗方法 提交用于R21的抗生素耐药细菌感染：铜绿假单胞菌（Pa），机会致病菌， 是医院感染的重大健康威胁，特别是对于免疫功能低下的患者， 烧伤、癌症、囊性纤维化或艾滋病患者。Pa和其他病原体产生抗生素耐药性 主要是通过群体感应（QS）机制，每年有超过23，000人死亡。解决 针对这一问题，最近发现了靶向假单胞菌多重毒力因子的分子（M64 调节器（MvfR）。这种在感染模型中经过验证的靶标表现出严重的溶解性问题， 更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具体重点。Pa的MvfR QS系统 是产生抗生素耐药性的关键。它控制多种细菌毒力因子的表达 与致病性有关，并引发对传统抗生素的耐药性。我们 MvfR-配体（激动剂或拮抗剂）结合X射线结构中的药效团对接研究表明， 药效团对接和构效关系（SAR）将有助于开发新的、有效的 MvfR抑制剂的药代动力学（PK）优于目前的抑制剂。在前期工作的基础上， 三个参与实验室（Jadhav博士，Deborah博士和Diggle博士），我们将使用，药效团对接， 和基于结构的合理药物设计来开发MvfR的小分子抑制剂。MvfR已经 在使用M64和其他类似物的小鼠模型中验证为抗菌靶标，但更有效的药物 需要更好的PK来开发该靶点的详细治疗潜力。在R21项目中，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， 在贾达夫博士的实验室里成功应用于相关目标将评价SAR中的化合物 在HTS中以1 μ M的单剂量对绿脓菌素抑制的活性， 德沃尔的实验室。然后，我们将优化的体外生化，细胞，选择性药代动力学特性， 开发先导化合物的抑制剂。将测试先导化合物的效力，以确定Pa毒力， Diggle博士实验室开发的体内猪肺（EVPL）感染模型。这种多学科合作 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。我们的长期目标是开发先进的候选药物， 作为新型抗生素对抗抗生素耐药性铜绿假单胞菌和其他细菌的临床前和临床评价 致病性革兰氏阴性菌。