Semi-synthesis of nisin: Tailoring antimicrobial activity and membrane-permeabilizing properties

Nisin belongs to the lantibiotics, a class of antimicrobial peptides. The presence of five consecutive lanthionines (thioether bridges) gives these peptides a rigid conformation that is highly important for their antibiotic activity. Nisin binds with its N-terminal part, consisting of the AB(C)-ring system, to lipid II thereby enabling the C-terminus, consisting of the knotted DE-ring, to form pores in the phospholipid membrane which ultimately leads to cell leakage and causes a collapse of the vital ion gradients across the membrane. Although the mechanism of antimicrobial activity is well described, the contribution of the individual lanthionines to the bioactivity still remains elusive. Therefore, we started a program to uncover nisin mimics in which the thioether was replaced by a dicarba-isostere based on alkyne/alkene ring-closing metathesis. Furthermore, via chemical/enzymatic cleavage techniques, native N-as well as C-terminal nisin fragments were obtained, and subsequently used in the semi-synthesis of biologically active nisin hybrids, containing native lanthionines as well as synthetic (cross) stapled lanthionine mimics. Herein, we describe the details of the rationale of design, the syntheses of the nisin fragments, including the chemoselective functionalization/ligation chemistries [1] to arrive at the desired nisin hybrids, as well as the biological/biochemical evaluation of their activity.