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.
Natural products that target lipid II, such as the lantibiotic nisin, are strategically important in the development of new antibacterial agents to combat the rise of antimicrobial resistance. Understanding the structural factors that govern the highly selective molecular recognition of lipid II by the N‐terminal region of nisin, nisin(1–12), is a crucial step in exploiting the potential of such compounds. In order to elucidate the relationships between amino acid sequence and conformation of this bicyclic peptide fragment, we have used solid‐phase peptide synthesis to prepare two novel analogues of nisin(1–12) in which the dehydro residues have been replaced. We have carried out an NMR ensemble analysis of one of these analogues and of the wild‐type nisin(1–12) peptide in order to compare the conformations of these two bicyclic peptides. Our analysis has shown the effects of residue mutation on ring conformation. We have also demonstrated that the individual rings of nisin(1–12) are pre‐organised to an extent for binding to the pyrophosphate group of lipid II, with a high degree of flexibility exhibited in the central amide bond joining the two rings.
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