Chemists Synthesize a Common Antibiotic

Researchers have synthesized the antibiotic nisin and have determined its crystal structure and the mechanism that controls its antibacterial enzyme activity.

Nisin is an inhibitory polycyclic peptide with 34 amino acid residues and is used as a food preservative. It contains the uncommon amino acids lanthionine, methyllanthionine, dehydroalanine, and dehydro-amino-butyric acid. These special amino acids are synthesized by posttranslational modifications. In these reactions, a ribosomally synthesized 57 amino acid peptide is converted to the final peptide. The unsaturated amino acids originate from serine and threonine.

Nisin is produced by fermentation using the bacterium Lactococcus lactis. Commercially it is obtained from natural substrates including milk and is not chemically synthesized. It is used in processed cheese production to extend shelf life by suppressing Gram-positive spoilage and pathogenic bacteria. Due to its highly selective spectrum of activity it is also employed as an agent in microbiologic media for the isolation of gram-negative bacteria, yeast, and molds.

Investigators at the University of Illinois (Urbana-Champaign, USA) used a single cyclase enzyme to re-create the synthetic process that normally occurs in L lactis. Results published in the March 10, 2006, issue of Science revealed that the NisC (nisin cyclase) enzyme catalyzes the formation of ten new chemical bonds in a stereochemically defined fashion, resulting in the five characteristic thioether rings required for nisin's biologic activity.

"Despite all the progress in synthetic chemistry, we cannot come close to making a compound like nisin efficiently,” said contributing author Dr. Wilfred A. van der Donk, professor of chemistry at the University of Illinois. "Synthetic chemists in the past needed 67 steps to make it, while nature uses just two enzymes. One of these is the cyclase whose activity we have demonstrated in this paper.”



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