Developing broad-spectrum cell wall inhibitors has proven challenging, particularly for Gram-negative bacteria, due to the protective outer membrane (OM) that limits drug access to the cell wall. However, synergistic therapy strategies, in which two agents are used in combination -either as fixed-dose or free-dose regimens -offer a promising solution. By pairing a non-OM permeable cell wall synthesis inhibitor (such as a glycopeptide or lantibiotic reviewed here) with a second compound that disrupts the OM, it may be possible to sensitize Gram-negative bacteria to the action of non-OM permeable cell wall synthesis inhibitors .