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Development of anti-virulence drugs by targeting the SaeRS two component system of Staphylococcus aureus

针对金黄色葡萄球菌SaeRS二组分系统开发抗毒力药物

基本信息

批准号：
9178642
负责人：
Taeok Bae
金额：
$ 16.6万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178642
关键词：
Animal Model Antibiotic Resistance Antibiotic Therapy Antibiotics Area Bacteria Binding Centers for Disease Control and Prevention (U.S.)Characteristics Clinical Complement Cytoplasmic Tail Development Drug Kinetics Drug Targeting Drug resistance Engineering Ensure Goals Growth Human Human Cell Line Immune system Infection Investigational Drugs Knowledge Lead Medical Metabolic Molecular Multi-Drug Resistance Pathogenicity Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phosphotransferases Production Proteins Proteomics Recruitment Activity Regimen Reporter Research Resistance Staphylococcal Infections Staphylococcus aureus System Testing Toxic effect Virulence Virulence Factors analog combat cost drug development drug quality efficacy testing extracellular high throughput screening improved in vivo inhibitor/antagonist innovation killings methicillin resistant Staphylococcus aureus mouse model mutant novel novel drug class novel strategies novel therapeutics pathogen public health relevance resistant strain screening sensor small molecule small molecule libraries stability testing success synergism trait

项目摘要

DESCRIPTION (provided by applicant): In Staphylococcus aureus, an important human pathogen, the SaeRS two component system (TCS) is essential for producing multiple virulence factors and enhancing the bacterium's survival in the host. In this application, a novel approach will be explored to develop anti-staphylococcal drugs by targeting the SaeRS TCS. Although conventional antibiotics directly kill bacteria and suffer from resistance problems, the new anti-staphylococcal agent will reduce only the pathogenic potential of the bacterium without killing; therefore, the agent is expected to complement the conventional antibiotics regimen without a resistance problem. In the R21 phase, we will identify potent two lead candidates of the Sae-inhibitor. In Aim 1, promising hit compounds will be identified by screening 80,000 small molecules. The identified hit compounds will be further examined for their toxicity on a human cell line. In Aim 2, through pharmacokinetic tests, the hit compounds with good metabolic stability and low in vivo toxicity will be selected. In Aim 3, the selected compounds will be furthr examined for their in vivo efficacy in a murine model of infection; and two lead candidates will be identified for the R33 phase study. Only when the two lead candidates satisfy the R21 milestones, will the R33 phase be undertaken. In the R33 phase, the two lead candidates will be further improved, while their potential as a novel anti- staphylococcal drug will be thoroughly examined. In Aim 1, derivatives of the lead candidates will be generated; then the derivatives with improved pharmacological traits will be identified through efficacy and stability tests. In Ai 2, the lead candidates will be examined for their synergy with conventional antibiotics in treating staphylococcal infections. In Aim 3, the mechanism by which the lead candidates inhibit the SaeRS TCS will be determined by identifying the direct binding targets of the lead candidates and isolating resistant mutants. Finally, in Aim 4, the lead candidates will be thoroughly examined for their potential to cause emergence of resistant mutants in a condition similar to clinical settings. The overall goal of this study is to determine whether the inhibitors of the SaeRS TCS can be a novel anti-staphylococcal drug in combating the antibiotic resistance problem of S. aureus.

描述（由申请人提供）：在金黄色葡萄球菌（一种重要的人类病原体）中，SaeRS二元系统（TCS）对于产生多种毒力因子并增强细菌在宿主中的存活至关重要。在此应用中，将探索一种通过靶向 SaeRS TCS 开发抗葡萄球菌药物的新方法。虽然传统抗生素直接杀死细菌并存在耐药性问题，但新型抗葡萄球菌药物只会降低细菌的致病潜力，而不会杀死细菌；因此，该药物有望补充传统的抗生素治疗方案，而不会出现耐药性问题。在 R21 阶段，我们将鉴定出两个有效的 Sae 抑制剂主要候选药物。在目标 1 中，将通过筛选 80,000 个小分子来鉴定有前景的热门化合物。鉴定出的命中化合物将进一步检查其对人类细胞系的毒性。目标2，通过药代动力学测试，筛选出代谢稳定性好、体内毒性低的命中化合物。在目标 3 中，将进一步检查所选化合物在小鼠感染模型中的体内功效；两名主要候选人将是确定用于 R33 阶段研究。只有当两个主要候选者满足 R21 里程碑时，R33 阶段才会开始。在R33阶段，两种主要候选药物将得到进一步改进，同时它们作为新型抗葡萄球菌药物的潜力将得到彻底检验。在目标 1 中，将生成主要候选者的衍生品；然后通过功效和稳定性测试来鉴定具有改善的药理特性的衍生物。在 Ai 2 中，将检查主要候选药物与传统抗生素在治疗中的协同作用葡萄球菌感染。在目标 3 中，将通过鉴定先导候选物的直接结合靶点并分离耐药突变体来确定先导候选物抑制 SaeRS TCS 的机制。最后，在目标 4 中，将彻底检查主要候选药物在类似于临床环境的条件下导致耐药突变体出现的潜力。本研究的总体目标是确定 SaeRS TCS 抑制剂是否可以成为解决金黄色葡萄球菌抗生素耐药性问题的新型抗葡萄球菌药物。