Overall Project Summary The ability to control bacterial infections with antibiotics has been one of the most important public health advancements in human history. Before the discovery of antibiotics and vaccines, infectious disease was the leading cause of death and constituted nearly 50% of deaths in the US alone. Now, infectious diseases as a cause of death barely makes the top ten and we now treat most bacterial infections as a nuisance rather than life-threatening diseases. Unfortunately, this is rapidly changing with the emergence of antibiotic resistant bacterial pathogens. Ultimately, our ability to develop new antibiotics faster than resistance amongst pathogens emerges has failed and many scientists expect we will experience a return to a pre-antibiotic era in which we cannot treat what are now easy to cure bacterial infections. Therefore, novel, non-antibiotic approaches to controlling bacterial infections are required and need to be explored. The main theme of the BCM-CARBIRU is to use microbiome-based approaches to control bacterial infections at mucosal surfaces. We will investigate ecological principles of microbial community inhibition of pathogen colonization as well as the use of bacteriophage for precision elimination of bacterial pathogens. Both approaches have advantages over the use of antibiotics in that they leave the native microbiome largely intact, avoiding the elimination of beneficial microbes along with the pathogens targeted by antimicrobials. We propose three projects, supported by two scientific cores and the administrative core, to explore and optimize microbiome-based strategies for the prevention and treatment of bacterial infections. Project 1. Discovery and mechanistic understanding of phage activity and synergism at host mucosal surfaces. Project 2. Defined microbial communities to prevent and eradicate infection by antibiotic resistant pathogens. Project 3. Nasal microbial consortia combat antibiotic-resistant bacteria. We expect two main outcomes from the execution of these projects. First, we expect to define and understand the ecological principles that are key for microbial communities and bacteriophage to function to control pathogens at mucosal surfaces. Second, we expect to have identified actionable phage and microbial communities that will be available for testing in human clinical trials at the end of the project periods. Together, these projects will capitalize on protective measures at the mucosal surface, which have existed for millennia prior to modern medicine, as we enter the next era of microbiome-based therapies.