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. Issue 64 (10th October 2019)

• Record Type: Journal Article
• Authors: Dickman, Rachael; Danelius, Emma; Mitchell, Serena A.; Hansen, D. Flemming; Erdélyi, Máté; Tabor, Alethea B.
• Is Part Of: Chemistry. Volume 25:Issue 64(2019)
• Page Start: 14572
• Page End: 14582
• Publication Date: 2019-10-10
• Subjects: antibiotics -- cyclic peptides -- lantibiotics -- NMR spectroscopy -- solid phase synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201902814
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : Lipid recognition : To probe the structural factors governing the highly selective molecular recognition of lipid II by the N‐terminal region of nisin, analogues of nisin(1‐12) were synthesised. NMR ensemble analysis of analogue and wild‐type structures reveals the favourable conformations available to these bicyclic ring structures.