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

项目总结

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.