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 CHAMPAIGN -- In the battle against
bacteria, researchers have scored a direct hit. They have made a
discovery that could shorten the road to new and more potent
antibiotics. The rapid
development of bacterial resistance to conventional antibiotics
(such as penicillin or vancomycin) has become a major public health
concern. Because resistant strains of bacteria can arise faster than
drug companies can create antibiotics, understanding how these
molecules function could help companies narrow their focus on
potential antibiotics and bring them to market sooner.
As reported in a paper accepted for
publication in the Journal of the American Chemical Society and
posted on its Web site, researchers have now deciphered the
molecular mechanism behind selective antimicrobial activity for a
prototypical class of synthetic compounds.
The compounds, which mimic
antimicrobial peptides found in biological immune systems, "function
as molecular 'hole punchers,' punching holes in the membranes of
bacteria," said Gerard Wong, a professor of
materials science and engineering,
physics, and
bioengineering at the U. of
I., and a corresponding author of the paper. "It's a little like
shooting them with a hail of nanometer-sized bullets – the
perforated membranes leak and the bacteria consequently die."
The researchers also determined why
some compounds punch holes only in bacteria, while others kill
everything within reach, including human cells.
"We can use this as a kind of Rosetta
stone to decipher the mechanisms of much more complicated
antimicrobial molecules," said Wong, who also is a researcher at the
university's Beckman Institute.
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"If we can understand the design rules
of how these molecules work, then we can assemble an arsenal of
killer molecules with small variations, and no longer worry about
antimicrobial resistance." In
a collaboration between the U. of I. and the University of
Massachusetts at Amherst, the researchers first synthesized a
prototypical class of antimicrobial compounds, then used synchrotron
small-angle X-ray scattering to examine the structures made by the
synthetic compounds and cell membranes.
Composed of variously shaped lipids,
including some that resemble traffic cones, the cell membrane
regulates the passage of materials in and out of the cell. In the
presence of the researchers' antimicrobial molecules, the
cone-shaped lipids gather together and curl into barrel-shaped
openings that puncture the membrane. Cell death soon follows.
The effectiveness of an antimicrobial
molecule depends on both the concentration of cone-shaped lipids in
the cell membrane, and on the shape of the antimicrobial molecule,
Wong said. For example, by slightly changing their synthetic
molecule's length, the researchers created antimicrobial molecules
that would either kill nothing, kill only bacteria, or kill
everything within reach.
 "By
understanding how these molecules kill bacteria, and how we can
prevent them from harming human cells, we can provide a more direct
and rational route for the design of future antibiotics," Wong said.
This work was supported by the
National Science Foundation, the National Institutes of Health and
the Office of Naval Research.
[Text copied from
University
of Illinois news release] |
