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

项目摘要 金黄色葡萄球菌是一种常见的人类病原体，可引起出了名的难治性感染。 并与较高的治疗失败率相关。随着这种病原体对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，减缓耐药发展。通过进一步推进我们的 了解抗生素如何在宿主环境中发挥作用，以及确定哪些因素 影响抗生素疗效，我们应该能够降低金黄色葡萄球菌感染的治疗失败率。 我们的初步数据显示，锰的限制增强了抗生素对细胞壁作用的杀灭作用 抗生素。此外，在低锰条件下生长的培养物显示出更高的自溶酶活性， 在肽聚糖分解和细胞壁动态平衡中很重要的酶。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受到病原体的限制。 钙保护素，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控减少，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 寄主的隔离使金黄色葡萄球菌对细胞壁作用的抗生素和限制锰的消耗敏感 通过宿主的饮食，可以提高抗生素治疗金黄色葡萄球菌感染的疗效。 在目标1中，我们将阐明由锰限制和锌离子驱动的抗生素增强的机制。 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。 和皮肤伤口模型。这些目标的完成将决定锰在抗生素中的作用 有效性。这个项目的意义源于需要了解抗生素是如何在 以及如何提高抗生素的效力，以减少治疗失败和减缓发展 抵抗。完成这项研究项目所获得的洞察力将有助于更大的 了解宿主相关因素如何影响抗生素治疗。 本建议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 随着对抗生素治疗的研究，为我提供了在 微生物学、实验设计和数据分析。因为我未来的目标包括专攻 传染病和在宿主-微生物相互作用领域的工作，这项建议将有助于我的 培养成为一名成功的导师、教师和内科科学家所必需的技能， 开展有可能对患者护理产生积极影响的微生物学研究。

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.