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.

Rachael Dickman,D Flemming Hansen,Máté Erdélyi,Serena A Mitchell,Alethea B Tabor,Emma Danelius

doi:10.1002/chem.201902814

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.

Highlights

Antibiotic resistant infections are becoming an increasing threat to global public health,[1] which has generated a renewed interest in natural products as a source of potent antimicrobial drugs
We have developed very effective solid-phase peptide synthesis methodology which we and others have applied to the 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 extended this work to prepare synthetic analogues of WT nisin(1–12), which can be compared with WT nisin(1–12) itself (1) (Figure 2). (Thr2, Ser5) analogue 2 was designed using the amino acids in the 2- and 5-positions that would be present in the biosynthetic precursor peptide, and that would undergo dehydration by the enzyme NisB in the producing organism.[50]

Summary

Introduction

Antibiotic resistant infections are becoming an increasing threat to global public health,[1] which has generated a renewed interest in natural products as a source of potent antimicrobial drugs. One such class of compounds is the lantibiotics: a family of gene-encoded antimicrobial peptides which are extensively post-translationally modified. The lantibiotics have complex cyclic structures generated by the thioether-bridged amino acids lanthionine (Lan) and methyllanthionine (MeLan), and frequently contain the a,b-unsaturated amino acids [b] Dr E. ErdØlyi The Swedish NMR Centre, Medicinaregatan 5, 40530 Gothenburg (Sweden)

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Conclusion