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Creation of antibiotic in test tube holds promise for better antibiotics

Scientists have made nisin, a natural antibiotic used for more than 40 years to preserve food, in a test tube for the first time using nature's toolbox. They also identified the structure of the enzyme that makes nisin and gives it its unique biological power.

The work -- published in the March 10 issue of Science -- sheds light on the almost magical manner in which nisin is made in nature and moves researchers closer to producing new antibiotics that would preclude the development and spread of antibiotic-resistant bacteria, said Wilfred A. van der Donk, a professor of chemistry, and Satish Nair, a professor of biochemistry, both at the University of Illinois at Urbana-Champaign.

Nisin, a peptide, contains 34 amino acid residues and the unusual amino acids lanthionine, methyllanthionine, dehydroalanine and dehydro-amino-butyric acid. The latter are made by post-translational modification of proteins.

Nisin works well against Gram-positive bacteria and food-borne pathogens that cause botulism and listeriosis because it punches holes into cell membranes and binds to essential molecules in the disease-causing bacteria. Hitting on at least two targets reduces the risk of resistance occurring, van der Donk said.

The researchers synthesized nisin simply in a test tube by using a single cyclase enzyme to re-create the process that normally occurs in a strain of the bacterium Lactococcus lactis found naturally in milk. They demonstrated how just one protein (NisC) makes 10 new chemical bonds in a stereochemically defined fashion. Specifically, they showed that NisC is responsible for the formation of five characteristic thioether rings required for nisin's biological activity.

"Despite all the progress in synthetic chemistry, we cannot come close to making a compound like nisin efficiently," van der Donk said. "Synthetic chemists in the past needed 67 steps to make it, while nature uses just two enzymes. One of these is the cyclase wh ose activity we have demonstrated in this paper."

The thioether rings vary in size from four to seven amino acids and provide sturdy protease-resistant bonds at precise locations. They account for nisin's robust resistance capability. It was theorized that one enzyme makes all five rings despite their very different sizes, but how it did so was like the mystery of a magic show, van der Donk said.

Nisin is one of numerous members of a family of compounds called lantibiotics, all of which are candidates for bioengineering into new pharmaceuticals, van der Donk said. The key is learning more about the enzymes involved in their biosynthesis. "Our work, while not explaining everything, has brought us much closer to that understanding, in particular the beautiful structure solved by the Nair group," he said.

Van der Donk previously had identified the molecular activity of another enzyme (LctM) responsible for naturally turning a small protein into a lantibiotic. That discovery, reported in Science in 2004, involved lacticin 481.

The new research also showed that NisC has unexpected structural similarities with mammalian farnesyl transferases, which are important for the activity of the RAS protein which when mutated is implicated in 25 percent of breast cancers. Preventing farnesylation possibly could prevent the cancerous effects, because the mutant protein would no longer be localized at the membrane, Nair said.

An accompanying Perspectives article in Science, written by chemist David W. Christianson of the University of Pennsylvania, suggests that nisin's five thioether rings may turn out to be golden "in the never-ending search for blockbuster antibiotics."


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Source:University of Illinois at Urbana-Champaign


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