SUMMARY This Harvard-wide Program on Antibiotic Resistance (HPAR) proposal outlines the design and function of a novel, multidisciplinary, collaborative partnership to develop new approaches for treating and preventing multidrug resistant MRSA and VRE infection. Although discovery and delivery of novel and promising new compounds to the development pipeline is a major overall goal, because this is an academic effort, we also will add to the scientific knowledge that underpins the novel inhibitors developed; add to the understanding of resistance; and develop novel new tools for studying host-pathogen interactions and multidrug resistant pathogens. This project is being proposed by an accomplished group of scientists with extensive experience in the biochemistry of cell wall biosynthesis and use of that information to design screens and new inhibitors; the molecular biology of model host systems and the use of those systems in novel ways for screening compounds that hit complex targets with minimal toxicity; the development and application of high throughput next generation technologies; and the pathogenesis, biology and clinical treatment of infection caused by multidrug resistant staphylococci and enterococci. This scientific expertise is complemented by substantial administrative experience. The goal of the HPAR Administrative Core therefore is to oversee the smooth implementation of the research plan and deployment of resources, and to foster the cohesive and well functioning whole to achieve goals that are greater than the sum of the individual projects. This will be accomplished by achieving the following Specific Aims: 1) Provide program management, oversight, and compliance assurance, 2) Facilitate interactions between participants from the various components of the Harvard Medical School (including faculty located on the Longwood Campus, at Massachusetts General Hospital, and the Massachusetts Eye and Ear Infirmary), and the Mylonakis lab now in part at Brown University – in a smooth and effective manner; 3) Provide critical infrastructure for fiscal management of the program; 4) Provide connectivity to and leverage other Harvard-wide initiatives, including the Microbial Sciences Initiative (MSI), and Catalyst Clinical and Translational Sciences Center; and 5) Provide a single point of contact and active coordination for on-going communication with NIAID, the Program Officer, and other NIAID staff and initiatives. The Administrative Core has managed the previous period in a way that led to a highly functioning, well integrated, and synergistic whole, and achieved additional aims generating resources and fostering data sharing with the greater scientific community. The proposed continuation period will build on these successes.