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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在20世纪80年代，我们证明了抑制细菌蛋白质合成的抗生素在治疗严重的A组链球菌和梭菌性肌坏死中比细胞壁活性剂具有更大的功效。毒素抑制已成为治疗由A组链球菌、组织毒性梭菌属和金黄色葡萄球菌引起的侵袭性感染的一个至关重要的目标。在其他危及生命的毒素介导的感染（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，尚未研究过抗生素诱导的毒素上调的影响。我们假设β-内酰胺类抗生素引起的毒性基因表达上调发生在几种临床重要的革兰氏阳性病原体中，并由青霉素结合蛋白参与后的共同细胞信号传导途径介导。 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S.金黄色。在《特定目标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C。艰难梭菌处理（万古霉素和甲硝唑）对梭菌产生毒素A和B的影响。很难 在具体目标3中，我们将比较存在和不存在亚抑制浓度β-内酰胺类抗生素时A组链球菌的生长期依赖性转录组。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组链球菌、产气荚膜梭菌和C.很难了解这些生物体中抗生素诱导的毒素上调的机制和免疫后果将使抗生素治疗更合理。

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.