BLRD Research Career Scientist Award Application

据估计，全世界每年有300万人死于沙门氏菌感染。多药联用 从2011年到2013年，临床沙门氏菌的耐药性增加了一倍以上。《世界卫生》 该组织将沙门氏菌列为全球12大抗药性细菌威胁之一 健康。这个研究职业科学家奖的目标是继续努力应用我们的 了解沙门氏菌毒力对开发抗多药耐药新抗生素的意义 细菌病原体。 沙门氏菌和其他病原菌对抗生素的耐药性在很大程度上是由 丙氨酸鸟苷、四磷酸鸟苷和Dks A蛋白。这两个调解人都绑定到 RNA聚合酶的第二通道，调节中枢代谢途径的转录和 各种毒力项目。我们将继续对其分子机制进行研究 鸟苷四磷酸和Dks A调节沙门氏菌的转录程序。研究报告 职业科学家奖还将允许我们开发抑制依赖Dks A的新型抗生素 细菌转录。DksA与RNA聚合酶二级通道的结合是竞争的 与GRE转录延伸因子结合。我们发现沙门氏菌需要GRE蛋白 这种革兰氏阴性杆菌的毒力和对抗生素的抗药性。我们计划将其描述为 GRE因子促进细菌致病和耐药的分子机制。 这些研究项目本质上是高度协作的，涉及与 亚特兰大退伍军人事务部东科罗拉多州医疗保健系统的调查人员 中心和退伍军人管理局安娜堡医疗系统。我计划继续培养 这些富有成效的合作。初级教师、研究生和博士后研究员的培训 也是本次研究职业科学家奖的重要组成部分。此外，在协作中 与东科罗拉多州退伍军人事务部的其他调查人员一起， 威斯康星-麦迪逊退伍军人医疗中心，我们将继续指导有前途的CDA-2候选人，以及 从而有助于培养下一代优秀的退伍军人管理局科学家。

Salmonella infections are responsible for an estimated 3 million annual deaths worldwide. Multidrug resistance among clinical Salmonella more than doubled from 2011 to 2013. The World Health Organization has ranked Salmonella as one of the top 12 antibiotic resistant bacterial threats to global health. The goal of this Research Career Scientist Award is to continue with our efforts to apply our knowledge of Salmonella virulence to the development of novel antibiotics against multidrug resistant bacterial pathogens. Resistance of Salmonella and other pathogenic bacteria to antibiotics is in great part regulated by the nucleotide alarmone guanosine tetraphosphate and the DksA protein. Both of these mediators bind to the secondary channel of RNA polymerase, regulating transcription of central metabolic pathways and a variety of virulence programs. We will carry on our research on the molecular mechanisms by which guanosine tetraphosphate and DksA regulate Salmonella transcriptional programs. The Research Career Scientist Award will also allow us to develop novel antibiotics that inhibit DksA-dependent bacterial transcription. Binding of DksA to the secondary channel of RNA polymerase is in competition with Gre transcription elongation factors. We have found that Gre proteins are needed for Salmonella virulence and the resistance of this Gram-negative rod to antibiotics. We plan to characterize the molecular mechanisms by which Gre factors promote bacterial pathogenesis and antibiotic resistance. These research projects are highly collaborative in nature, involving scientific interactions with investigators at the Veterans Affairs Eastern Colorado Healthcare System, the Atlanta VA Medical Center and the Veterans Administration Ann Arbor Healthcare System. I plan to continue fostering these productive collaborations. Training of junior faculty, graduate students and postdoctoral fellows are also important components of this Research Career Scientist Award. Moreover, in collaboration with other investigators at the at the Veterans Affairs Eastern Colorado Healthcare System and Wisconsin-Madison VA Medical Center, we will continue mentoring promising CDA- 2 candidates, and thus help train the next generation of outstanding VA scientists.