Teixobactin is a promising antibacterial agent with potent bactericidal activity, particularly against antibiotic-resistant bacterial strains. Despite extensive studies on teixobactin binding to lipid II, it remains unclear how the antibiotic achieves such potency given that its primary target is the pyrophosphate and sugar moiety of lipid II. An important mechanistic question is how does teixobactin avoid non-specific interactions with other molecules that contain phosphates or pyrophosphates within the cell? To address this, we employed well-tempered metadynamics simulations with PLUMED and GROMACS to construct two-dimensional free energy surfaces of teixobactin interactions with lipid II and other peptidoglycan precursors in both solution and membrane environments. We find that hydration of the pyrophosphate group on lipid II plays a key role in defining the affinity of teixobactin for its lipid target. The reduced solvent accessibility of the lipid II headgroup in the membrane environment results in the formation of a tightly bound teixobactin complex that sits in a deep energy well. In contrast to this, interaction of the lipid II headgroup with teixobactin in solution leads to frequent binding and unbinding events with shallow minima and a low energy barrier for association/dissociation. These findings provide mechanistic insights into teixobactin’s mode of selectivity and highlight how membrane-associated hydration environments enable stable binding to lipid II while minimizing nonspecific interactions.
Herron et al. (Sun,) studied this question.