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: 10057424
• 负责人: Gopal P Jadhav
• 金额: $ 22.74万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057424
• 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; 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.

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