Exploring Conformations of the Teixobactin-Lipid II Complex in Membrane

Abstract

Teixobactin is a recently discovered antibiotic that works against gram-positive bacteria without detectable resistance. The bactericidal mechanism of teixobactin is believed to be the inhibition of cell wall synthesis due to the binding to lipid II and lipid III, which likely takes place at the pyrophosphate moiety that shared by both targets. Despite numerous chemical analogs of teixobactin have been synthesized and functionally assessed, and the pharmacophore of one analog has been identified, detailed structural information is still lacking for the conformations of teixobactin and lipid II in their complex. Here we use molecular modeling and multiple sets of microsecond-scale molecular dynamics simulations to create atomic models of teixobactin-lipid II complex at the membrane surface. Two major lipid II binding conformations of teixobactin have been captured, and both show pyrophosphate binding by the backbone amides near the C-terminal cyclic depsipeptide (D-Thr8—Ile11) ring, as well as by the side chains of Ser7 and the unique allo-enduracididine. Interestingly, the major difference between the two conformations is the swapping of two groups of hydrogen bond donors that coordinate one of the lipid II phosphates, which results in opposite orientations of lipid II binding between two conformations. In addition, regardless of the detailed phosphate-binding interactions, residues D-allo-Ile5 and Ile6 always function as membrane anchors in both conformations. Based on the teixobactin-lipid II interactions captured in their complexes, as well as their partition depths at the membrane surface, we propose that the bactericidal mechanism of teixobactin is to arrest cell wall synthesis by selectively inhibiting the transglycosylation of peptidoglycan, while the transpeptidation is possibly unaffected. This pyrophosphate caging mechanism of lipid II inhibition appears to be similar to some lantibiotics, but different from that of vancomycin or bacitracin.