The design of bi-functional or chimeric molecules targeting both the OM and peptidoglycan synthesis, however, introduces significant challenges. Key among these is understanding the structure-activity relationship (SAR) for such complex agents. Multi-scale modeling approaches are essential to elucidate how these drugs interact with various bacterial cell structures, including the OM, inner membrane (IM), lipid II, and the peptidoglycan layer. Through an integrated approach involving multi-scale modeling, synergistic drug combinations, and SAR studies, a framework may be setup to systematically broaden the antimicrobial spectrum of (lipo-)glycopeptides and lantibiotics towards Gram-negative bacteria.