Bacterial ribosome heterogeneity and gene expression

项目摘要 随着抗生素耐药性在全球范围内的增加，迫切需要新的药物， 对抗细菌感染。开发新的抗菌剂的方法包括抑制 基因表达和抑制毒力因子产生的重要步骤。总体 我实验室研究项目的重点是了解细菌细胞 调节基因表达，最终确定新的目标， 发展该奖项资助的研究将利用拉姆齐实验室的 细菌遗传学方面的专业知识和最先进的技术，以研究 多个细菌物种中的核糖体异质性。拉姆齐实验室发现了一种 核糖体蛋白bS 21的特异性同源物，该蛋白在一种病毒中控制毒力基因表达。 细菌病原体这些发现表明，核糖体的异质性，这是显着的 药物靶点，可以导致基因表达的变化。核糖体的异质性对 基因翻译、基因表达和药物功效通常没有被很好地理解， 我们知识中的关键差距。在未来五年，我们建议继续研究， 了解核糖体异质性对多种细菌物种的影响。拟议 工作是创新的，因为它需要一个严格的，简化的方法来检查一个不好的- 理解核糖体异质性的来源，并对翻译产生物种特异性影响， 阐明翻译的基本特征，并为新型抗菌剂的设计提供信息。我们 目标包括确定多种bS 21同源物如何控制基因表达，为什么 bS 21在某些细胞中是必需的，以及bS 21如何有助于抗生素敏感性。我们期望我们 这项工作将使我们能够清楚地了解核糖体组成和功能之间的联系， 结果，因为我们将限制核糖体异质性的复杂性，以改变一个单一的 核糖体蛋白，bS 21。预计未来的工作将包括开发新的，具体的屏幕 核糖体抑制剂和研究bS 21或其他独立核糖体来源的功能 在这些和/或其他生物体中的异质性。最终，我们的研究将提供关键的见解， 核糖体功能，基因表达，并可能确定新的抗菌药物的目标。

PROJECT SUMMARY As antibiotic resistance increases globally, there is an urgent need for new drugs to combat bacterial infections. Approaches to developing new antimicrobials include inhibiting essential steps in gene expression and inhibiting virulence factor production. The overarching focus of the research program in my laboratory is to understand how bacterial cells regulate gene expression, to ultimately identify novel targets for antimicrobial development. The research funded by this award will leverage the Ramsey laboratory’s expertise in bacterial genetics and state of the art technologies to examine the impacts of ribosome heterogeneity in multiple bacterial species. The Ramsey laboratory identified a specific homolog of the ribosomal protein bS21 that governs virulence gene expression in a bacterial pathogen. These findings suggest that heterogeneity in ribosomes, which are significant drug targets, can lead to changes in gene expression. The impacts of ribosome heterogeneity on translation, gene expression, and drug efficacy are generally not well understood and represent key gaps in our knowledge. Over the next five years, we propose to continue our studies to understand the effects of ribosome heterogeneity on multiple bacterial species. The proposed work is innovative because it takes a rigorous, reductionist approach to examine one poorly- understood source of ribosome heterogeneity with species-specific impacts on translation to elucidate fundamental features of translation and inform the design of novel antimicrobials. Our goals include determining how multiple bS21 homologs function to govern gene expression, why bS21 is essential in some cells, and how bS21 contributes to antibiotic sensitivity. We expect our work will allow us to make clear connections between ribosome composition and functional outcomes, as we will limit the complexity of ribosomal heterogeneity to changes in a single ribosomal protein, bS21. Expected future work will include developing screens for novel, specific ribosome inhibitors and studying the function of bS21 or other independent sources of ribosome heterogeneity in these and/or other organisms. Ultimately our studies will provide key insights into ribosome function, gene expression, and may identify novel targets for antimicrobial drugs.