The discovery of antibiotics and their development into therapeutic agents represents one of the most important advances in the history of medicine. However, the evolution of antibiotic resistance is greatly limiting antibiotic usefulness The specter of a post-antibiotic era looms heavy in the field of infectious diseases. Thus, there is an urgent need new antibiotics that are effective against important human pathogens that are now resistant to most, if not all, commonly used antibiotics. Bacteria from the order Actinomycetales have been the most important source of antibiotics. Yet, while the sequenced genomes of these bacteria suggest that there they have the potential to produce many more antibiotic molecules, only a fraction of the predicted molecules have been detected in the lab. In contrast to most culturing techniques that involve only one species, we have discovered that culturing bacteria in multi-species communities stimulates the production of diverse and unique small molecules. With this in mind, in order to stimulate the production of novel antimicrobial compounds, we have developed a method for growing complex multi-species communities over extended periods of time. These communities are grown in an environment that allows them to secrete molecules into a liquid medium that can easily be sampled and assayed for the production of antibiotics that are effective against pathogens such as methicillin resistant Staphylococcus aureus (MRSA) and carbapenem resistant Klebsiella pneumoniae. We specifically propose to develop a large-scale screen for the discovery of novel antibiotic activities produced by Actinomycetes grown as multi-species communities. We also propose to identify and optimize the production of the molecules that display antibiotic activity. These aims will hopefully result in the identification of new antibiotics that are effective against currently problematic multi-drug resistant pathogens.