Researchers at SSRL Map New Antibiotic Target
By Kate Metropolis
Addressing one of the world’s pressing health problems, scientists
working at SSRL have now obtained detailed information about an enzyme
that plays a key role in bacterial self-defense. This advance could lead
to a new approach to combating bacterial illnesses, which cause more
than 10 million deaths a year.
|Model of a
novel class of antibacterials, superimposed over an example of
the data used to discover them.
(Image Courtesy of Robert Scott)
After the penicillin family of antibiotics
was discovered and developed in the 1940’s, illness and deaths from
infectious disease declined dramatically. However, an antibiotic works
against specific bacteria for only so long before random mutations (that
all bacteria undergo) reduce or eliminate the effectiveness of that
Today, according to the Centers for Disease Control, virtually all
important bacterial infections throughout the world are rapidly becoming
resistant to the antibiotics that have been used to treat them for
decades. The Encyclopedia of Life Sciences puts the minimum yearly cost
of antibiotic resistance in the U.S. alone at $150 million.
Recently, scientists from the University of Georgia, Utah State
University, and Guilford Pharmaceuticals carried out studies at SSRL
that could enable drug designers to gain the upper hand—at least for a
while—by developing a new class of antibiotics.
Their work explored a novel antibacterial target—a step in the recipe
most bacteria use to create the rigid wall that surrounds and protects
individual bacterial cells. Two important components of the bacteria’s
cell wall are synthesized by the enzyme DapE. Deleting the gene that
encodes DapE has been shown to be lethal to certain bacteria, including
the strain that causes stomach ulcers and that also appears to be a
major cause of stomach cancer. So, inhibiting the DapE enzyme looks like
a promising approach for drug designers.
Because mammals use a different recipe to make their cell walls, an
antibiotic that inhibits the DapE enzyme should be toxic to bacteria but
not to human cells.
The researchers used a technique (analysis of extended x-ray absorption
fine structure) possible only with synchrotron light to map the atomic
neighborhood of the chemically active part of the DapE enzyme. This
information is important for identifying a chemical component that can
lock onto this site and prevent the enzyme from doing its job in
production of the cell wall.
The investigators also obtained additional information useful in drug
design—a view of the enzyme bound to inhibiting molecules and a glimpse
of the enzyme in action.
The work was reported last year in the Journal of the American Chemical
Society, vol. 125, no. 48, p. 14654 (http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/2003/125/i48/pdf/ja036650v.pdf)