Chemical Synthesis of the Lantibiotic Lacticin 481 Reveals the Importance of Lanthionine Stereochemistry

• Published in: Journal of the American Chemical Society Vol. 135; no. 19; pp. 7094 - 7097
• Main Authors: Knerr, Patrick J, van der Donk, Wilfred A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.05.2013; Amer Chemical Soc
• Subjects: Alterations; Amino Acid Sequence; Amino acids; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antiinfectives and antibacterials; Bacteriocins - chemical synthesis; Bacteriocins - chemistry; Bacteriocins - pharmacology; Biological; Chemistry; Chemistry, Multidisciplinary; Communication; Crosslinking; Lactococcus lactis - chemistry; Lactococcus lactis - drug effects; Molecular Sequence Data; Natural products; Physical Sciences; Science & Technology; Stereochemistry; Stereoisomerism; Synthesis (chemistry); NISIN; ANALOGS; NATURAL-PRODUCTS; AMINO-ACIDS; BIOSYNTHESIS; LIPID-II; SOLID-PHASE; SYNTHETASE; LACTOCIN S; PEPTIDE
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja4014024

Lantibiotics are a family of antibacterial peptide natural products characterized by the post-translational installation of the thioether-containing amino acids lanthionine and methyllanthionine. Until recently, only a single naturally occurring stereochemical configuration for each of these cross-links was known. The discovery of lantibiotics with alternative lanthionine and methyllanthionine stereochemistry has prompted an investigation of its importance to biological activity. Here, solid-supported chemical synthesis enabled the total synthesis of the lantibiotic lacticin 481 and analogues containing cross-links with non-native stereochemical configurations. Biological evaluation revealed that these alterations abolished the antibacterial activity in all of the analogues, revealing the critical importance of the enzymatically installed stereochemistry for the biological activity of lacticin 481.