AI-3 Inhibitors as treatment for bacterial infections

AI-3 抑制剂治疗细菌感染

基本信息

批准号：
7626424
负责人：
VANESSA SPERANDIO
金额：
$ 137.21万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7626424
关键词：
Adrenergic Receptor Adverse effects Air Animal Model Animals Antibiotics Antimicrobial Resistance Area Bacteria Bacterial Infections Basic Science Binding Biochemical Biochemical Pathway Biodistribution Biological Biological Process Cells Characteristics Chemicals Clinical Research Communication Complex Data Development Dose Drug Design Drug Formulations Drug Kinetics Environment Epinephrine Escherichia coli EHEC Escherichia coli O157 Event Excretory function Food Poisoning Francisella tularensis Frequencies Gene Expression Generations Genes Genetic Transcription Goals Growth Half-Life Hormones Human In Vitro Infant Infection Laboratories Lead Libraries Light Mammalian Cell Membrane Metabolism Minor Modification Molecular Multi-Drug Resistance Mus Norepinephrine Oral Organism Oryctolagus cuniculus Outcome Pathogenesis Pathogenicity Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phosphotransferases Plants Preparation Process Program Development Property Reaction Research Research Personnel Resistance development Role Safety Salmonella Salmonella infections Signal Transduction Signaling Molecule Small Molecule Chemical Library Structure Structure-Activity Relationship Surface Syndrome System Systemic infection Technology Temperature Testing Therapeutic Toxic effect Translating Treatment Protocols Tularemia Virulence Work absorption analog antimicrobial bacterial resistance base biothreat combat design drug candidate drug development drug discovery drug efficacy drug metabolism drug resistant bacteria enteric pathogen gastrointestinal good laboratory practice in vivo infected vector rodent inhibitor/antagonist innovation insight killings microorganism novel novel strategies pathogen pre-clinical preclinical study predictive modeling pressure programs quorum sensing receptor scaffold sensor small molecule tool trait

项目摘要

DESCRIPTION (provided by applicant): Bacteria communicate with each other via a system of signals known as quorum sensing. In recent years it has been demonstrated that this complex system of communication can include not just bacterial produced signals, but also host derived signals to control gene expression of virulence in pathogenic species. This proposal combines the expertise of five laboratories to develop compounds that compromise bacterial quorum sensing. By targeting quorum sensing we decrease the possibility of the development of resistance as it is not an essential biological process and thus negative selective pressure will be minor. We have identified a promising compound that inhibits the virulence of enterohemorrhagic E. coli and Salmonella species causing numerous food poisoning syndromes, as well as Francisella tularensis, the causative agent of tularemia by interfering with quorum sensing. These three diverse organisms, and potentially many others, can all be targeted by a single compound due to the presence of a widely conserved membrane bound receptor protein. Preliminary data suggests that this compound is specific for bacterial systems at concentrations in the picomolar range and has no obvious adverse effects on the host. In addition to the single compound that we have significant preliminary data for a number of alternative distinct compounds have also been identified and may be further developed. Our consortium contains the expertise to rationally develop this or an alternative compound into effective broad-spectrum inhibitor of virulence rendering the bacteria harmless.

描述（由申请人提供）：细菌通过称为群体感应的信号系统相互通信。近年来，已经证明这种复杂的通讯系统不仅可以包括细菌产生的信号，还可以包括宿主衍生的信号来控制致病物种毒力的基因表达。该提案结合了五个实验室的专业知识来开发损害细菌群体感应的化合物。通过针对群体感应，我们降低了产生抗性的可能性，因为它不是一个重要的生物过程，因此负选择压力将很小。我们发现了一种有前途的化合物，它可以通过干扰群体感应来抑制引起多种食物中毒综合征的肠出血性大肠杆菌和沙门氏菌，以及土拉菌病的病原体土拉热弗朗西斯菌。由于存在广泛保守的膜结合受体蛋白，这三种不同的生物体以及可能的许多其他生物体都可以被单一化合物靶向。初步数据表明，该化合物在皮摩尔浓度范围内对细菌系统具有特异性，并且对宿主没有明显的不利影响。除了单一化合物之外，我们还确定了许多替代的不同化合物的重要初步数据，并且可能会进一步开发。我们的联盟拥有专业知识，可以合理地将这种化合物或替代化合物开发成有效的广谱毒力抑制剂，使细菌无害。