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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.
�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.
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