This disclosure provides modified antimicrobial agents, for example modified defensin polypeptides. In one embodiment, compositions including a modified arginine residue, such as an ADP-ribosylated and/or ribosylated alpha defensin polypeptide, are provided. Also provided are methods of modulating an immune response using the modified defensin polypeptides. In one embodiment, a method is provided for modulating an antimicrobial activity. In another embodiment, a method is provided for inhibiting a cytotoxic activity. Also disclosed are methods for treating diseases in a subject that are associated with an immune response, such as inflammatory and pulmonary diseases, using the disclosed modified defensin polypeptides.