Docking on Lipid II-A Widespread Mechanism for Potent Bactericidal Activities of Antibiotic Peptides

Natural product antibiotics usually target the major biosynthetic pathways of bacterial cells and the search for new targets outside these pathways has proven very difficult. Cell wall biosynthesis maybe the most prominent antibiotic target, and ß-lactams are among the clinically most relevant antibiotics. Among cell wall biosynthesis inhibitors, glycopeptide antibiotics are a second group of important drugs, which bind to the peptidoglycan building block lipid II and prevent the incorporation of the monomeric unit into polymeric cell wall. However, lipid II acts as a docking molecule for many more naturally occurring antibiotics from diverse chemical classes and likely is the most targeted molecule in antibacterial mechanisms. We summarize current knowledge on lipid II binding antibiotics and explain, on the levels of mechanisms and resistance development, why lipid II is such a prominent target, and thus provide insights for the design of new antibiotic drugs.