The discovery of new antibiotics to combat the spread of drug-resistant organisms is imperative to avoid a ‘post-antibiotic era’. Natural products which target the bacterial cell wall precursor lipid II (<b>1</b>), such as the lantibiotic nisin (<b>2</b>), provide promising lead compounds for development of novel antimicrobial agents. However, to exploit the highly selective interaction between the lipid II pyrophosphate and the nisin N-terminus, a better understanding of the structural basis of the recognition is required. We therefore sought to explore the relationship between the amino acid sequence of nisin(1-12) and the adopted solution conformation of the peptide using NMR ensemble analysis. To this end, two novel simplified analogues of nisin(1-12) bearing dehydro residue replacements were prepared by solid-phase peptide synthesis, and the resulting bicyclic peptides were analysed using NAMFIS (NMR Analysis of Molecular Flexibility In Solution). This technique, in contrast to average structure calculation protocols, deconvolutes time averaged NMR data allowing identification of all conformers present in solution and their molar fractions. Using this method, we have investigated the effect of residue mutation on lantibiotic ring conformation. We have also shown that wild-type nisin(1-12) displays a degree of pre-organisation for binding to lipid II, and that a high degree of flexibility is exhibited around the amide bond joining the rings in both nisin(1-12) and analogues. These results will inform the design of novel lantibiotics bearing structurally simplified lipid II-binding regions.

Conformational analysis of lantibiotic peptides

2019 Fall National Meeting

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