IMPACT OF ANTIBIOTICS ON EXPRESSION OF EXOTOXIN GENES IN GRAM POSITIVE PATHOGENS

抗生素对革兰氏阳性病原体外毒素基因表达的影响

• 批准号: 8167435
• 负责人: Dennis L Stevens
• 金额: $ 13.16万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167435
• 关键词: Ampicillin; Antibiotic Therapy; Antibiotics; Bacterial Proteins; Cell Wall; Ciprofloxacin; Clindamycin; Clostridium difficile; Clostridium perfringens; Computer Retrieval of Information on Scientific Projects Database; Diarrhea; Exotoxins; Funding; Gas Gangrene; Gene Expression; Gene Expression Profile; Genes; Goals; Grant; Growth; Immune; Immune system; Infection; Institution; Life; Mediating; Metronidazole; Monobactams; Nafcillin; Organism; Penicillin-Binding Proteins; Phase; Production; Protein Biosynthesis; RNAIII; Regulatory Pathway; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Source; Staphylococcus aureus; Streptococcus pyogenes; Toxic Shock Syndrome; Toxin; United States National Institutes of Health; Up-Regulation; Vancomycin; beta-Lactams; pathogen; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the 1980's we demonstrated that antibiotics that inhibit bacterial protein synthesis have greater efficacy than cell wall active agents in the treatment of severe group A streptococcal and clostridial myonecrosis. Toxin suppression has become a critically important goal in the treatment of aggressive infections due to group A streptococcus, histotoxic clostridial species and Staphylococcus aureus. The impact of antibiotic-induced toxin upregulation has not been examined in the context of other life-threatening, toxin-mediated infections such as clostridial gas gangrene, streptococcal toxic shock syndrome or Clostridium difficile-associated diarrhea (CDAD). We hypothesize that upregulation of toxic gene expression by Beta-lactam antibiotics occurs in several clinically impotant Gram positive pathogens and is mediated by a common Cell Signaling pathway following engagement of penicillin-binding proteins. In Specific Aim 1 we will elucidate the roles of agr, RNAIII and other toxin regulatory pathways in nafcillin-induced upregulation of exotoxin production in S. aureus. In Specific Aim 2 we will compare the effects of antibiotics associated with triggering CDAD (clindamycin, ampicillin and ciprofloxacin) and those currently used for C. difficile treatment (vancomycin and metronidazole) on production of Toxins A and B by C. difficile. In Specific Aim 3 we will compare the growth phase-dependent transcriptome of group A streptococcus in the presence and absence of subinhibitory concentrations of beta-lactam antibiotics. In specific Aim 4 we will investigate innate immune system recognition of and response to beta-lactam-treated S aureus, group A streptococcus, C perfringens and C. difficile. Understanding the mechanisms responsible for, and the immune consequences of, antibiotic-induced toxin upregulation in these organisms will enable a more rational approach to antibiotic therapy.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 在 20 世纪 80 年代，我们证明抑制细菌蛋白质合成的抗生素在治疗严重的 A 族链球菌和梭菌性肌坏死方面比细胞壁活性剂更有效。毒素抑制已成为治疗 A 族链球菌、组织毒性梭菌和金黄色葡萄球菌引起的侵袭性感染的一个极其重要的目标。抗生素引起的毒素上调的影响尚未在其他危及生命的毒素介导的感染（例如梭菌气性坏疽、链球菌中毒性休克综合征或艰难梭菌相关性腹泻（CDAD））的背景下进行研究。我们假设β-内酰胺抗生素对毒性基因表达的上调发生在几种临床上重要的革兰氏阳性病原体中，并且是由青霉素结合蛋白参与后的常见细胞信号传导途径介导的。 在具体目标 1 中，我们将阐明 agr、RNAIII 和其他毒素调节途径在萘夫西林诱导的金黄色葡萄球菌外毒素产生上调中的作用。在具体目标 2 中，我们将比较与触发 CDAD 相关的抗生素（克林霉素、氨苄青霉素和环丙沙星）和目前用于艰难梭菌治疗的抗生素（万古霉素和甲硝唑）对艰难梭菌产生毒素 A 和 B 的影响。 在特定目标 3 中，我们将比较在存在和不存在亚抑制浓度的 β-内酰胺抗生素的情况下 A 组链球菌的生长阶段依赖性转录组。在具体目标 4 中，我们将研究先天免疫系统对 β-内酰胺处理的金黄色葡萄球菌、A 族链球菌、产气荚膜梭菌和艰难梭菌的识别和反应。了解这些生物体中抗生素诱导的毒素上调的机制及其免疫后果将使抗生素治疗方法更加合理。