Molecular Recognition of Lipid II by Lantibiotics: Synthesis and Conformational Studies of Analogues of Nisin and Mutacin Rings A and B

In response to the growing threat
posed by antibiotic-resistant
bacterial strains, extensive research is currently focused on developing
antimicrobial agents that target lipid II, a vital precursor in the
biosynthesis of bacterial cell walls. The lantibiotic nisin and related
peptides display unique and highly selective binding to lipid II.
A key feature of the nisin–lipid II interaction is the formation
of a cage-like complex between the pyrophosphate moiety of lipid II
and the two thioether-bridged rings, rings A and B, at the N-terminus
of nisin. To understand the important structural factors underlying
this highly selective molecular recognition, we have used solid-phase
peptide synthesis to prepare individual ring A and B structures from
nisin, the related lantibiotic mutacin, and synthetic analogues. Through
NMR studies of these rings, we have demonstrated that ring A is preorganized
to adopt the correct conformation for binding lipid II in solution
and that individual amino acid substitutions in ring A have little
effect on the conformation. We have also analyzed the turn structures
adopted by these thioether-bridged peptides and show that they do
not adopt the tight α-turn or β-turn structures typically
found in proteins.