Synthesis of Bicyclic Alkene‐/Alkane‐Bridged Nisin Mimics by Ring‐Closing Metathesis and their Biochemical Evaluation as Lipid II Binders: toward the Design of Potential Novel Antibiotics

Abstract

This report describes the design, synthesis, and biochemical evaluation of alkene‐ and alkane‐bridged AB(C)‐ring mimics of the lantibiotic nisin. Nisin belongs to a class of natural antimicrobial peptides, and has a unique mode of action: its AB(C)‐ring system binds to the pyrophosphate moiety of lipid II. This mode of action was the rationale for the design of smaller nisin‐derived peptides to obtain novel potential antibiotics. As a conformational constraint the thioether bridge was mimicked by an alkene‐ or alkane isostere. The peptides of the linear individual ring precursors were synthesized on solid support or in solution, and cyclized by ring‐closing metathesis in solution with overall yields of between 36 and 89 %. The individual alkene‐bridged macrocycles were assembled in solution by using carbodiimide‐based synthesis protocols for the corresponding AB(C)‐ring mimics. These compounds were tested for their binding affinity toward lipid II by evaluation of their potency to inhibit nisin‐induced carboxyfluorescein release from large unilamellar vesicles. It was found that these AB(C)‐ring mimics were not able to induce membrane leakage; however, they acted by inhibiting nisin‐induced carboxyfluorescein release; this indicates their affinity toward lipid II. These results imply that an alkene or alkane moiety is a suitable thioether bridge mimic.

Analysis of membrane interactions of antibiotic peptides using ITC and biosensor measurements

“…To consider the role of lipid II as molecular target and its impact on binding intensity, 0.1 mol% lipid II was added to the matrix lipids. In accordance to other peptide/model membrane studies [27][28][29][30][31][32][33] and to avoid non-specific binding of the cationic antimicrobial peptides to the membrane surface, DOPC was initially selected as membrane lipid. As depicted in Fig 2A, [34,35], the gallidermin structure ( Fig.…”

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

“…4 macrocycle in a ratio of 2:1 after 16 h of refluxing in CH 2 Cl 2 [110,111]. Dicarba AB-and ABC-ring mimics of nisin were able to recognize its natural substrate lipid II, although with a tenfold reduced affinity compared to its native counterpart [114,115], while the DE-ring mimics were found to be devoid of membrane permeabilizing interactions [112,116].…”

Estrogenic Activity of Alkyl(thio)phenols and 4,4'-thiodiphenol Formed from Degradation of Commercial Insecticides

“…4B, Ghalit et al reported that the conformational constraint of a thioether-part, -S-, is a similar to that of alkene or alkane. 40) In the present study, the pS-alkyl phenols and TDP can be regarded as positive compounds in terms of the estrogenic activity from the findings based on two bioassays. As a plausible reason for this positive activity, it should be noted that bioisosteric replacement between TDP and 4,4 -dihydroxystilbene (DHS) is valid, as shown in Fig.…”