Selective Agents to Block Virulence in Gram-negative Pathogens

阻断革兰氏阴性病原体毒力的选择性药物

基本信息

批准号：
8267480
负责人：
ROBERT MARTIN BLUMENTHAL
金额：
$ 18.19万
依托单位：
UNIVERSITY OF TOLEDO
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/8267480
关键词：
Adopted Affect Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacterial Antibiotic Resistance Bacterial Infections Bioinformatics Cause of Death Cessation of life Complement Developed Countries Development Disease Effectiveness Enzymatic Biochemistry Enzymes Genes Goals Gram-Negative Bacteria Growth Health Care Costs Human Infection Infectious Agent Lead Libraries Ligase Measures Metabolic Pathway Metabolism Methionine Methods Microbial Biofilms Molecular Target Morbidity - disease rate Natural Immunity Organism Orthologous Gene Pathogenesis Pharmaceutical Preparations Phase Positioning Attribute Production Property Reporter Genes Research Resistance Screening procedure Signal Pathway Signal Transduction Testing Therapeutic Intervention Validation Viola Virulence Virulence Factors Wages War Work analog bacterial resistance design experience high throughput screening inhibitor/antagonist innovation killings meetings methyl group microbial mortality pathogen pathogenic bacteria pressure prevent programs promoter quorum sensing response selective prevention weapons

项目摘要

DESCRIPTION (provided by applicant): The spectacular rise of bacterial antibiotic resistance is a serious problem, particularly among Gram-negative pathogens, increasing morbidity, mortality and healthcare costs. Despite over a century of intense effort focused on killing pathogenic bacteria, these organisms have developed and shared increasingly inventive ways to overcome the best drugs we have been able to produce. There is growing evidence that a different approach, aimed at inhibiting virulence without inhibiting growth per se, can prevent or cure disease without inevitably leading to resistance. Our long term goal is to develop approaches that will selectively prevent the onset of virulence in bacterial pathogens. Our objective for this application is to develop selective inhibitors that block virulence and inhibit biofilm formation in Gram-negative human pathogens without otherwise interfering with their growth. Our central hypothesis is that biosynthesis of the quorum sensing (QS) molecules that trigger a virulence response can be selectively inhibited, without affecting the essential aspects of bacterial metabolism, by altering the common precursor for these QS molecules. Because these organisms will remain viable, but functionally avirulent, there will be much weaker selective pressure for resistance to QS inhibition. We plan to accomplish our project goals through the following complementary initial specific aims: (1) design and test alternative substrates and inhibitors for target enzymes that selectively block the production of QS molecules; and (2) use a new screening method to identify QS inhibitors on a broader scale. Once these aims have been achieved we will move to Phase II of this project, which involves: (1) focusing our quorum sensing inhibitor development towards specific pathogenic species; and (2) testing the ability of these inhibitors to synergistically increase the effectiveness of currently used antibiotics. The contribution of our proposed research will be the development of an approach that leads to new drugs while minimizing selection for bacterial resistance. This work is significant because it is designed to validate an alternative approach that does not rely on microbial death to overcome bacterial infections. PUBLIC HEALTH RELEVANCE: Mortality from infections is the second leading cause of death worldwide, and is still the third leading cause in industrialized countries. The major threat comes from bacterial pathogens that have evolved resistance to most classes of antibiotics. An approach that can block virulence in Gram-negative bacteria while minimizing selection for resistance will lead to a new paradigm in the treatment of infections.

描述（由申请人提供）：细菌抗生素耐药性的壮观升高是一个严重的问题，尤其是在革兰氏阴性病原体中，发病率，死亡率和医疗保健成本提高。尽管有一个多世纪的激烈努力着重于杀死致病细菌，但这些生物已经发展并共享了越来越有创造力的方法来克服我们能够生产的最佳药物。越来越多的证据表明，旨在抑制毒力而不抑制生长本身的不同方法可以预防或治愈疾病，而不可避免地导致抗药性。我们的长期目标是开发将有选择地防止细菌病原体中毒力发作的方法。我们对此应用的目的是开发选择性抑制剂，以阻断革兰氏阴性人类病原体中的毒力并抑制生物膜形成，而不会另外干扰其生长。我们的中心假设是，可以选择性地抑制触发毒力反应的法定感测（QS）分子的生物合成，而不会通过改变这些QS分子的共同前体来影响细菌代谢的基本方面。由于这些生物将保持可行但功能性无动于衷，因此选择性压力将抑制QS抑制作用。我们计划通过以下互补的初始特定目的来实现项目目标：（1）设计和测试替代性底物和抑制剂，以选择性地阻止QS分子的产生；（2）使用一种新的筛选方法在更广泛的规模上识别QS抑制剂。一旦实现了这些目标，我们将进入该项目的第二阶段，其中涉及：（1）将我们的法定人数感应抑制剂的发展集中在特定的病原体上；（2）测试这些抑制剂有协同作用的能力，从而提高了当前使用的抗生素的有效性。我们提出的研究的贡献将是开发一种导致新药的方法，同时最大程度地减少对细菌耐药性的选择。这项工作很重要，因为它旨在验证不依赖微生物死亡来克服细菌感染的替代方法。公共卫生相关性：感染死亡率是全球死亡的第二大原因，仍然是工业化国家的第三大主要原因。主要威胁是从对大多数类别的抗生素抗性发展的细菌病原体。一种可以阻止革兰氏阴性细菌毒力的方法，同时最大程度地减少耐药性选择的方法将导致感染治疗的新范式。