Synthesis and Bioactivity of Diastereomers of the Virulence Lanthipeptide Cytolysin

Abstract

Cytolysin, a two-component lanthipeptide comprising cytolysin S (CylLS″) and cytolysin L (CylLL″), is the only family member to exhibit lytic activity against mammalian cells, in addition to synergistic antimicrobial activity. A subset of the thioether crosslinks of CylLS″ and CylLL″ have LL-stereochemistry instead of the canonical DL-stereochemistry in all previously characterized lanthipeptides. The synthesis of a CylLS″ variant with DL stereochemistry is reported. Its antimicrobial activity was found to be decreased but not its lytic activity against red blood cells. Hence, the unusual LL-stereochemistry is not responsible for the lytic activity.

A Chemical Biology Approach to Understanding Molecular Recognition of Lipid II by Nisin(1–12): Synthesis and NMR Ensemble Analysis of Nisin(1–12) and Analogues

“…Several different approaches to the chemical synthesis of lantibiotics have been reported over the past 20 years . We have developed very effective solid‐phase peptide synthesis methodology which we and others have applied to the synthesis of individual rings of lantibiotics, overlapping rings and to the total synthesis of complete lantibiotics . We have previously reported the solid‐phase synthesis of the individual A and B rings of nisin and of the related lantibiotic, mutacin I, and have investigated the conformational properties of these isolated rings and synthetic analogues by NMR.…”

“…[41,42] We have developed very effective solid-phase peptides ynthesis methodology which we and others have appliedtothe synthesis of individual rings of lantibiotics, [43,44] overlapping rings [45] and to the total synthesis of complete lantibiotics. [46][47][48][49] We have previously reported the solid-phase synthesis of the individual Aa nd Br ings of nisin and of the related lantibiotic, mutacin I, [25] and have investigated the conformationalp roperties of these isolated rings ands ynthetic analogues by NMR. We have now extended this work to prepares ynthetic analogues of WT nisin (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), which can be compared with WT nisin(1-12) itself (1)( Figure 2).…”

Progress in Lanthionine and Protected Lanthionine Synthesis

“…[55] To gether with Lan 114, those mutuallyo rthogonally protected b-Me-Lan allow the SPPS synthesis of ap eptide chain containing overlapping lanthionine bridges.O ther naturally occurring lanthipeptides such as lacticin4 81 and cytolysin were similarly prepared. [23,79] The case of an analogue of epilancin 15X presented hereafter exemplifies the particular challenge of building overlapping lanthionines bridges in ap eptide and the use of the mutually orthogonally protected Lan 99, 101 and 114.…”

Solid-phase peptide synthesis of analogues of the N-terminus A-ring fragment of the lantibiotic nisin: Replacements for the dehydroalanine (Dha) residue at position 5 and the first incorporation of a thioamide residue

“…2 However, its stability and solubility decrease considerably at physiological pH which precludes its use as a human therapeutic. The A and B rings of the N-terminus of nisin (nisin [3][4][5][6][7][8][9][10][11][12] ) are critical to its overall biological activity where it binds to the lipid II moiety inhibiting the biosynthesis of the bacterial cell wall. 3 It is known that at physiological pH the two Dha residues at positions 5 and 33 are cleaved by hydrolysis.…”

“…10 These syntheses required the reliable preparation of significant quantities of orthogonally protected lanthionines and -methyllanthionines with tailored protecting groups suitable for SPPS.…”