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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." |
