Identifying the role of manganese limitation in antibiotic killing of Staphylococcus aureus

项目摘要 金黄色葡萄球菌（Staphylococcus aureus）是一种常见的人类病原体，其引起的感染是众所周知的难以治疗的。 解决并与高治疗失败率相关。随着这种病原体的抗生素耐药性的上升 正在迅速耗尽治疗选择，迫切需要确定提高抗生素疗效的因素 以降低治疗失败率并减缓耐药性的发展。通过促进我们的 了解抗生素如何在宿主环境中发挥作用，以及确定 影响抗生素疗效，我们应该能够降低S.金黄色葡萄球菌感染 我们的初步数据表明，锰限制增强了抗生素对细胞壁作用的杀伤作用， 抗生素此外，在低锰条件下生长的培养物显示出自溶素的活性增加， 在肽聚糖分解和细胞壁稳态中起重要作用的酶。重要的是，在宿主入侵期间， 必需金属如锰通过宿主蛋白的作用而被限制在病原体之外 钙卫蛋白，其用于限制病原体传播和控制感染。 我们假设锰限制导致自溶素的负调节减少，导致增加 自溶素活性和对细胞壁作用抗生素的敏感性增加。我们预测锰 宿主的隔离使S.金黄色葡萄球菌细胞壁作用抗生素和限制锰消耗 通过宿主的饮食，可以增加抗生素治疗S.金黄色葡萄球菌感染 在目标1中，我们将阐明由锰限制驱动的抗生素增效机制， 目的2我们将研究锰限制对小鼠菌血症抗生素治疗成功的影响 和皮肤创伤模型。这些目标的实现将决定锰在抗生素中的作用 有效性这个项目的重要性源于需要了解抗生素如何在体内起作用。 如何提高抗生素的疗效，以减少治疗失败，减缓 阻力从完成这项研究项目中获得的见解将有助于实现更大的 了解宿主相关因素如何影响抗生素治疗。 本建议书中详述的研究和培训计划将整合宿主-微生物相互作用的研究 随着抗生素治疗的研究，为我提供了发展先进技术技能的机会， 微生物学、实验设计和数据分析。因为我未来的目标包括 传染病和宿主-微生物相互作用领域的工作，这项建议将有助于我 发展成为一名成功的导师、教师和医生-科学家所需的技能， 开展微生物学研究，有可能对患者护理产生积极影响。

Project Summary Staphylococcus aureus is a common human pathogen responsible for infections that are notoriously difficult to resolve and associated with high rates of treatment failure. As the rise of antibiotic resistance for this pathogen is quickly depleting treatment options, there is a critical need to identify factors which improve antibiotic efficacy in order to decrease the rates of treatment failure and slow the development of resistance. By furthering our understanding of how antibiotics work within the host environment, as well as identifying factors which influence antibiotic efficacy, we should be able to reduce the rate of treatment failure for S. aureus infections. Our preliminary data shows that manganese limitation potentiates the antibiotic killing of cell-wall acting antibiotics. Furthermore, cultures grown in low-manganese conditions showed increased activity of autolysins, enzymes important in peptidoglycan breakdown and cell wall homeostasis. Importantly, during host invasion, essential metals such as manganese are limited from the pathogen through action of the host protein calprotectin, which serves to limit pathogen spread and control infection. We hypothesize that Mn limitation results in decreased negative regulation of autolysins, leading to increased autolysin activity and increased susceptibility to cell-wall acting antibiotics. We predict that manganese sequestration by the host sensitizes S. aureus to cell-wall acting antibiotics and that by limiting Mn consumed through the diet of the host, we can increase the efficacy of antibiotics in the treatment of S. aureus infections. In Aim 1 we will elucidate the mechanism of antibiotic potentiation as driven by manganese limitation and in Aim 2 we will examine the effect of manganese limitation on antibiotic treatment success in murine bacteremia and skin wound models. Completion of these aims will determine the role of manganese availability in antibiotic effectivity. The significance of this project stems from the need to understand how antibiotics work within the host and how antibiotic efficacy can be improved to decrease treatment failure and slow the development of resistance. The insight gained from the completion of this research project will contribute towards a greater understanding of how host-associated factors influence antibiotic treatment. The research and training plan detailed in this proposal will integrate the study of host-microbe interactions with the study of antibiotic treatment, providing me the opportunity to develop advanced technical skills in microbiology, the design of experiments, and data analysis. As my future goals include subspecializing in infectious disease and working in the field of host-microbe interactions, this proposal will aid in my development of the skill set necessary to become a successful mentor, teacher, and physician-scientist, conducting research in microbiology that has the potential to positively impact patient care.