The Rχ-04 program employs a de novo approach to develop novel antibiotics that are active against Gram-negative bacteria. This program exploits the peptidyl transferase region of the 50S subunit, which is the catalytic region of the ribosome and the binding site of many chemically distinct classes of antibiotics, including oxazolidinones (e.g., linezolid), lincosamides (e.g., clindamycin), phenyl propanoids (e.g., chloramphenicol), pleuromutilins (e.g., retapamulin), macrolides/ketolides (e.g., azithromycin) and sparsomycin. After synthesizing fewer than 200 compounds, we have created five completely novel series of compounds targeting two novel sites that show good antibacterial activity against a number of clinically important multi drug resistant Gram-negative pathogens.