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.
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.
Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
Nourdin
N
Ghalit
John F
JF
Reichwein
Hans W
HW
Hilbers
Eefjan
E
Breukink
Dirk T S
DT
Rijkers
Rob M J
RM
Liskamp
D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry*; D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D039301:Computers, Molecular; D003500:Cyclization; D015195:Drug Design; D005452:Fluoresceins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D009561:Nisin / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D011104:Polyisoprenyl Phosphate Oligosaccharides; D013237:Stereoisomerism; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000378:metabolism
D000473:Alkanes; D000475:Alkenes; D000900:Anti-Bacterial Agents; D005452:Fluoresceins; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D011104:Polyisoprenyl Phosphate Oligosaccharides; D053835:Unilamellar Liposomes; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D009561:Nisin; C024098:6-carboxyfluorescein; C017251:1,2-oleoylphosphatidylcholine