Towards the native binding modes of Lipid II targeting antibiotics

The alarming rise of antimicrobial resistance (AMR) imposes severe burdens on health care systems and the economy worldwide, urgently calling for the development of novel antibiotics. Antimicrobial peptides could be ideal templates for next-generation antibiotics due to their low propensity to develop resistance. An especially promising branch of antimicrobial peptides target Lipid II, the precursor of the bacterial peptidoglycan network. In order to develop these peptides into clinically applicable compounds, detailed information on their pharmacologically relevant modes of action is of critical importance. Here, we review the current understanding on the binding mode of a selection of Lipid II targeting peptides, and we highlight shortcomings in our molecular understanding that, at least partly, relate to the widespread use of artificial membrane mimics for structural studies of membrane-active antibiotics. In particular, we showcase on the example of the antimicrobial peptide nisin that the native cellular membrane environment can be critical to understand the physiologically relevant binding mode.