Determining bacterial RNA polymerase functionalities required for sigma factor specific escape from antibiotic action.

基础研究对社会和经济目标的贡献最大，目标是能够从更多的基础知识中受益的领域，如报告所述：1)纳尔逊，R.R.，2004年。市场经济和科学公地。政策33：455-471；2)罗森伯格、内森和理查德·R·纳尔逊(1994)，“美国大学和工业中的技术进步”，政策23：323-348；3)罗森伯格，内森(1982)，“科学有多外生？”《黑箱内幕》(纽约：剑桥大学出版社)，第141-159页。在这项建议中，我们寻求建立细菌如何对用于控制其在感染环境中的生长的试剂做出反应。了解细菌对抗菌剂的相对敏感性的基础对于管理活体和人类中的感染非常重要，并为管理感染和设计新的抗菌剂提供策略。抗微生物药物的一个有效靶点是基因表达的中央机制，即解码DNA的酶RNA聚合酶(RNAP)。了解各种RNAP全酶对抗菌剂的相对敏感性的基础是重要的，并说明了如何解释内在的敏感性水平--这是具有实际意义的事情。应用的动机是基础知识中的差距，这仅仅是因为在评估针对细菌RNAP的抗菌剂的有效性时，通常不考虑RNAP状态的范围--通过使用不同的称为西格玛因子的辅助因子来反映。各种RNAP对抗菌剂的反应是重要的，它说明了如何解释生物体或基因组的内在敏感性水平。新的证据表明，转录因子，如RNAP sigma因子，可以是形成耐药组的一组因子的成员。这表明，细胞的基本组成可以赋予抗菌剂显著的不敏感性，而不会调用特定耐药机制的作用。由于转录因子，如RNAP sigma因子可以是耐药组的成员，我们希望弄清楚这些因子是如何赋予RNAP对抗菌药的耐受性的。预计所产生的结果将扩大我们对针对细菌RNAP的抗生素的作用的了解，以及RNA如何发挥作用以获取DNA中的遗传信息。我们将使用我们建立的方法来检查DNA解码过程中的哪些步骤对抗生素的作用敏感或耐药，特别是那些正在成为抗菌治疗新候选药物的药物。

Basic research best contributes to social and economic goals when targeted to areas that can benefit from additional fundamental knowledge, as reported in: 1) Nelson, R.R., 2004. The market economy and the scientific commons. Res. Policy 33: 455-471; 2) Rosenberg, Nathan, and Richard R. Nelson (1994), "American Universities and Technical Advance in Industry," Res. Policy 23:323-348; 3) Rosenberg, Nathan (1982), "How Exogenous is Science?" in Inside the Black Box (NY: Cambridge University Press), p. 141-159. In this proposal we seek to establish how bacteria respond to the agents that are used to control their growth in infection settings.Knowing the basis of relative sensitivities of bacteria to antimicrobials is important for managing infection in live stock and in humans, and informs strategies to manage infection and design new antimcrobials. One validated target for antimicrobials is the central machinery of gene expression, the enzyme RNA polymerase (RNAP) that decodes the DNA. Knowing the basis of relative sensitivities of various RNAP holoenzymes to antimicrobials is important, and speaks to how the intrinsic levels of sensitivity may be accounted for - something of practical significance.The application was motivated by the gap in basic knowledge which currently exists simply because the range of RNAP states - reflected by the use of differing accessory factors called sigma factors - are not often taken into account when assessing the efficacies of antimicrobials that target bacterial RNAPs. The response of various RNAPs to antimicrobials is important, and speaks to how the intrinsic levels of sensitivity of an organism or gene set might be accounted for. Emerging evidence shows that transcription factors, such as RNAP sigma factors, can be members of a group of factors that form the resistome. Showing that is, that the basic make up of the cell that can confer significant insensitivity to an antimicrobial without invoking the action of specific resistance mechanisms. Since transcription factors such as RNAP sigma factors can be members of a resistome, we wish to work out how these factors confer upon RNAP tolerance to antimicrobials. Outcomes arising are expected to enlarge our knowledge of the action of antibiotics that target bacterial RNAP, as well as how the RNA functions to access the genetic information in DNA. We will use methods established by us to examine which steps in the DNA decoding process are sensitive or resistant to the actions of antibiotics, in particular those agents which are emerging as new candidates for antimicrobial therapies.