A conformationally constrained fused tricyclic nisin AB-ring system mimic toward an improved pyrophosphate binder of lipid II
2014
Harmsen, Rianne A.G. | Ghalit, Nourdin | Kemmink, Johan | Breukink, Eefjan | Liskamp, Rob M.J. | Rijkers, Dirk T.S.
The bacteria-specific membrane component lipid II is essential for bacterial cell wall synthesis. A tricyclic nisin mimic was designed and synthesized in which both thioether moieties were mimicked by an alkane-bridge, as well as the introduction of a third conformational constraint consisting of a macrocyclic lactam-bridge between the N-terminus and the B-ring. The newly designed tricyclic AB-ring mimic was found to bind lipid II since it was able to inhibit nisin-induced membrane leakage in a dose-dependent manner. These results imply that the tricyclic AB-ring mimic may form a novel class of lead structures for the development of nisin-based peptide antibiotics.
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