Methods and compositions are provided to modulate the activity of Perforin-2. Provided herein are various components of the Perforin-2 activation pathway. In specific embodiments, inhibitors of the various components of the Perforin-2 activation pathway are provided which may be employed in various methods, including, but not limited to, the diagnosis and treatment of diseases associated with gut inflammation. Methods of screening for Perforin-2 inhibitors are also provided. Further provided are compounds that increase the ubiquitination of Perforin-2 and thereby increase Perforin-2 activity. Various methods for increasing Perforin-2 activity and for the treatment of infectious disease, in particular bacteria and antibiotic-resistant bacteria, are also provided.
