Molecular Analysis of Bacterial Adaptive Response to Host Reactive Species

感染性腹泻每年折磨着10亿人，约占人类总数的4%。 世界各地的死亡人数。肠沙门氏菌是人类感染性腹泻的常见原因，通常 困扰着现役军人和退伍军人。沙门氏菌是最常见的细菌之一 对抗生素有抗药性的菌株。抗生素耐药危机正在成为EPIC的临床难题 比例，因为正在筹备中的治疗化合物的数量正在减少。未来的预防措施 而抗药性细菌的治疗方法将极大地受益于鉴定 病原体的分子靶标。在过去的20年里，只有4种新化合物被引入 在临床上，所有这些都代表了通过对分子的基本了解而确定的新机制 发病机制。正如对所有人类病原体一样，对RNA聚合酶的精确调控控制着 沙门氏菌发病机制的基本方面，以及抗生素耐药程序的表达。我们的 研究表明，Dks A和Gre因子与RNA聚合酶的变构相互作用 调节沙门氏菌致病机制和抗生素耐药性的重要方面。拟议的研究将 阐明DNAK/DNAJ伴侣对调节Dks A相互作用的机制 与RNA聚合酶结合，从而参与沙门氏菌的基本毒力计划。我们还将 描述GRE因子与RNA聚合酶二级通道的结合如何提供 沙门氏菌致病机制和抗生素耐受性的调控水平此前并不令人怀疑。 具体地说，我们将测试与GRE因子相关的转录校对在 沙门氏菌对NADPH氧化酶固有杀菌活性的抵抗力。我们的调查 也将表征GRE因子如何调节至关重要的III型分泌系统的表达 沙门氏菌的细胞内生活方式，同时增强对氨基糖苷类抗生素的耐药性 有毒细菌翻译。我们的研究将有助于未来疗法的合理发展 对各种革兰氏阴性、抗药性细菌的抗药性，这些细菌导致高发病率和 现役军人、退伍军人及其家属的死亡率。

Infectious diarrhea afflicts a billion people a year and is responsible for approximately 4% of all human deaths worldwide. Salmonella enterica are common causes of infectious diarrhea in humans, and often plague active military servicemen and veterans. Salmonella are among the most frequent bacterial isolates resistant to antibiotics. The antibiotic resistance crisis is becoming a clinical problem of epic proportions, as the number of therapeutic compounds in the pipeline is dwindling. Future prophylactic and therapeutic approaches against drug resistant bacteria will greatly benefit from the identification of molecular targets in pathogens. During the last 20 years only 4 novel compounds have been introduced in the clinic, all of which represent new mechanisms identified through basic understanding of molecular pathogenesis. As holds true for all human pathogens, precise regulation of RNA polymerase controls essential aspects of Salmonella pathogenesis, and the expression of antibiotic resistant programs. Our investigations have shown that allosteric interactions of DksA and Gre factors with RNA polymerase regulate vital facets of Salmonella pathogenesis and antibiotic resistance. The proposed research will elucidate the mechanisms by which the DnaK/DnaJ chaperone couple regulates interactions of DksA with RNA polymerase, thereby engaging fundamental Salmonella virulence programs. We will also characterize how binding of Gre factors to the secondary channel of RNA polymerase provides a previously unsuspected level of regulation of Salmonella pathogenesis and antibiotic tolerance. Specifically, we will test the role that the transcriptional proofreading associated with Gre factors plays in resistance of Salmonella to the bactericidal activity inherent to the NADPH oxidase. Our investigations will also characterize how Gre factors modulate the expression of a type III secretion system that is vital to the intracellular lifestyle of Salmonella, while bolstering resistance to aminoglycoside antibiotics that poison bacterial translation. Our investigations will aid in the rational development of future therapies against a variety of Gram-negative, antibiotic resistant bacteria that cause high rates of morbidity and mortality in active servicemen, veterans and their families.