Molecular level discovery could play role in development of new antibiotics

01/26/04

CHAMPAIGN, Ill. -- Chemists at the University of Illinois at Urbana-Champaign have uncovered the molecular activity of an enzyme responsible for naturally turning a small protein into a potent antibiotic known as a lantibiotic.

The finding is described in the Jan. 30 issue of the journal Science. The research details how the enzyme performs two biosynthetic reactions that lead to the formation of fused cyclic structures required for antimicrobial activity. The discovery unlocks a door that could lead to a new line of antibiotic compounds based on nature's machinery, said Wilfred A. van der Donk, a professor of chemistry at Illinois.

The work was done using lacticin 481, a lantibiotic produced by one of several strains of Lactococcus lactis, a bacterium used in cheese production. Other lantibiotics are used to preserve other dairy products and canned vegetables. The lantibiotic nisin has been used for more than 50 years as an alternative to chemicals in food preservation in more than 40 countries without the development of significant antibiotic resistance.

"The use of antibiotics is an important area of medicine, because pathogenic bacteria are always in the environment," van der Donk said. "It's important to renew our arsenal of compounds that combat pathogens. With the development of resistance -- not just the kind that occurs through evolution but also the kind potentially created in biological weapons by terrorists -- we will always need new antibiotics."

The breakthrough in van der Donk's lab came in March 2003, when his doctoral student Lili Xie, now at the Harvard Medical School, noticed catalytic activity in the material she was investigating. Van der Donk had been pursuing such activity for six years. Many other labs have tried since the late 1980s, when the genes involved in nisin's biosynthetic pathway were sequenced, but efforts to make analogs in vitro had failed.

Lantibiotics are ribosomally synthesized and modified into a bacteria-fighting form after translation. One type of lantibiotics is modified by two proteins, while another type, scientists have proposed, is able to complete the transformation, forming cyclic regions with sturdy protease-resistant bonds at precise locations, with just one enzyme.

The finding in van der Donk's lab and subsequent analyses in the research laboratory of Neil L. Kelleher, a professor of chemistry and co-principal investigator, confirms that one enzyme, LctM, alone can complete the modification.

The researchers were led to LctM, which is involved in the biosynthesis of lacticin 481, through trial and error as they tried to manipulate a peptide substrate. LctM, acting in the presence of adenosine triphosphate and ionized magnesium, selected specific serines and threonines for modification, allowing for a correct final structure of the material.

It was reported in 1999 that lantibiotics such as nisin are effective and elude resistance because they work like a double-edged sword. They form holes in the cell membranes and also bind to intermediate targets of a disease-causing bacterium. Hitting on two targets simultaneously reduces the risk of resistance occurring, van der Donk said.

"We are interested in antibiotics that are used commercially and that are not chemically made but derived from organisms, such as bacteria, that make them for us," he said. "If nature makes these materials, wouldn't it be great to understand and use the machinery that nature uses to make compounds ourselves? By having this purified system, we can modify the substrate of the enzyme that makes a lantibiotic and make antibiotic analogs that nature cannot make. This really opens an avenue to engineer antibiotics and look for active compounds that we can access using the machinery we've found."

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