Small Molecule Inhibitors of P. aeruginosa Quinolone (Pqs) Quorum Sensing

铜绿假单胞菌喹诺酮 (Pqs) 群体感应的小分子抑制剂

基本信息

批准号：
8268842
负责人：
DEREK S TAN
金额：
$ 24.38万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8268842
关键词：
Acquired Immunodeficiency Syndrome Address Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial Drug Resistance Binding Biochemical Biochemistry Biological Assay Biological Factors Biological Markers Burn injury Cancer Patient Cause of Death Cell Communication Cells Cellular Assay Coenzyme A Cystic Fibrosis Development Drug Design Drug resistance Enzymes Evaluation Gene Expression Generations Genes Goals Gram-Negative Bacteria Growth HIV Immunocompromised Host In Vitro Individual Infection Interdisciplinary Study Laboratories Lead Ligase Memorial Sloan-Kettering Cancer Center Microbial Biofilms Microbiology Mutation Nosocomial Infections Organic Chemistry Organic Synthesis Pathogenicity Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Process Prodrugs Production Property Pseudomonas Pseudomonas aeruginosa Public Health Quinolones Resistance Route Seminal Series Structure System Text Therapeutic Variant Virulence Virulence Factors Work analog anthranilate antibiotic efflux bacterial genetics base combat design drug development homoserine lactone in vivo inhibitor/antagonist intercellular communication methyl anthranilate mouse model novel pathogen pathogenic bacteria preclinical evaluation quorum sensing receptor research clinical testing response small molecule

项目摘要

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that poses a significant public health threat in the context of nosocomial infections, particularly for immunocompromised patients such as burn victims, cancer patients, and individuals having cystic fibrosis or AIDS. P. aeruginosa is also prone to antibiotic resistance, through both intrinsic and acquired mechanisms. Thus, there is a great need for the development of novel anti-Pseudomonas drugs that address unexploited targets, and this is a specific focus of this RFA. To address this problem, we propose herein to develop novel small molecule antibacterials that target the P. aeruginosa quinolone (Pqs) quorum sensing system. This is a pharmacologically validated target in a mouse model of infection and is distinct from acyl homoserine lactone (Las, Rhl) quorum sensing systems. Quinolones are small molecules that are biosynthesized by the bacteria and used in cell-cell signaling. They control expression of a variety of bacterial virulence factor genes that are associated with pathogenicity but are not required for bacterial viability or growth. As such, novel antibacterials that target such virulenc factors are thought less likely to elicit drug resistance compared to traditional bacteriotoxic and bacteriostatic antibiotics. Building upon extensive previous work from the three participating laboratories (Tan, Rahme, Pesci), we will use mechanism- and structure-based rational drug design to develop small molecule inhibitors of PqsA, an anthraniloyl-CoA synthetase that catalyzes an essential step in P. aeruginosa quinolone biosynthesis. PqsA has been validated as an effective antibacterial target in a mouse model using simple substrate analogues, but more potent and specific inhibitors are required to exploit fully the therapeutic potential of this target. In the R21 phase, we will synthesize first-generation inhibitors using a rational design strategy that has been applied successfully to related targets in the Tan lab, then evaluate their activities in biochemical and cellular assays for PqsA activity and quinolone production established previously in the Pesci and Rahme labs. In the R33 phase, we will optimize the biochemical, cellular, and pharmacological properties of the inhibitors to develop lead compounds that will then be advanced to in vivo evaluation in established mouse models of P. aeruginosa infection in the Rahme lab. This multidisciplinary collaboration comprises the necessary combined expertise in synthetic organic chemistry, medicinal chemistry, biochemistry, pharmacology, and microbiology. Our long- term goals are to develop one or more advanced candidates for further preclinical and clinical evaluation as novel antibiotics to combat P. aeruginosa and potentially other pathogenic Gram-negative bacteria. PUBLIC HEALTH RELEVANCE: Pseudomonas aeruginosa is a pathogenic bacteria that poses a significant public health threat to hospitalized, immunocompromised patients such as burn victims, cancer patients, and individuals having cystic fibrosis or AIDS. The goal of this project is to develop novel antibacterial drugs to combat P. aeruginosa infections by targeting a bacterial process called quorum sensing, which is associated with virulence and pathogenicity and may be less prone to eliciting antibacterial resistance.

描述（由申请人提供）：铜绿假单胞菌是一种机会主义的革兰氏阴性病原体，在医院感染的背景下构成了重大的公共卫生威胁，尤其是对于免疫功能低下的患者，例如烧伤受害者，癌症患者，癌症患者和患有囊性纤维化或AIDS的人。铜绿假单胞菌也通过内在和获得的机制都容易发生抗生素耐药性。因此，非常需要开发针对未开发靶标的新型抗假单胞菌药物，这是该RFA的特定重点。为了解决这个问题，我们在这里建议开发针对铜绿假单胞菌奎诺酮（PQS）群体传感系统的新型小分子抗菌。这是小鼠感染模型中有药理学验证的靶标，与酰基同素内酯（LAS，RHL）群体传感系统不同。喹诺酮是小分子，由细菌生物合成并用于细胞 - 细胞信号传导。他们控制与致病性相关但不是细菌生存能力或生长所必需的。因此，与传统的细菌毒素相比抑菌抗生素。在三个参与实验室（TAN，RAHME，PESCI）的大量工作的基础上，我们将使用基于机制和基于结构的理性药物设计来开发PQSA的小分子抑制剂，PQSA是一种炭疽菌-COA合成酶，在P.ereguginosa Quinolone Biosyses中催化了基本步骤。使用简单的底物类似物，在小鼠模型中，PQSA已作为有效的抗菌靶标进行了验证，但是需要更有效和特定的抑制剂才能充分利用其治疗潜力目标。在R21阶段，我们将使用已成功应用于TAN实验室中相关目标的合理设计策略合成第一代抑制剂，然后评估其在PQSA活性的生物化学和细胞分析中的活性，以及先前在PESCI和RAHME LABS中建立的Quinolone产生。在R33阶段，我们将优化抑制剂的生化，细胞和药理学特性，以开发铅化合物，然后在RAHME LAB中已建立的铜绿假单胞菌感染的既定小鼠模型中进行体内评估。这种多学科的合作包括合成有机化学，药物化学，生物化学，药理学和微生物学的必要综合专业知识。我们的长期目标是开发一个或多个先进的候选物，以进一步的临床前和临床评估，作为对抗铜绿假单胞菌和潜在的其他病原革兰氏阴性细菌的新型抗生素。公共卫生相关性：铜绿假单胞菌是一种致病性细菌，对住院的，免疫功能低下的患者（例如烧伤受害者，癌症患者和患有囊性纤维化或艾滋病）构成了重大的公共卫生威胁。该项目的目的是通过靶向称为Quorum Sensing的细菌过程来开发新型抗菌药物来对抗铜绿假单胞菌感染，该过程与毒力和致病性有关，并且可能不太容易引起抗细菌抗性。