UCSD Biochemists Discover Bacteria’s
Research May Aid Design
of Novel Antibiotics
By Sherry Seethaler
at the University of California, San Diego have determined what
factors turn on protein production in bacteria, a finding that
provides new targets for the development of antibiotics.
In the study, published
in the April 7 issue of the journal Molecular Cell,
researchers Sean Studer and Simpson Joseph in UCSD’s Department
of Chemistry and Biochemistry report how the messenger RNA instructions
to make a protein are unfolded in a bacterial cell, so that
they can be read by the cell’s protein-making machinery.
Since unfolding the instructions is an essential step in the
making of a protein, the researchers say that drugs designed
to interfere with this step would make ideal antibiotics.
being manufactured according to mRNA instructions
Credit: Sean Studer, UCSD
strains of bacteria on the rise, there is a crisis in the management
and treatment of these infections throughout the world,”
said Simpson Joseph, a professor of chemistry and biochemistry
who led the study. “Our results will provide insights
for developing novel antibiotics that target the messenger RNA
unfolding process in disease-causing bacteria.”
Messenger RNA (mRNA)
feeds through a ribosome—protein factory in a cell—like
a tape through a teletype machine. There the RNA instructions
are read and a protein is assembled, one amino acid building
block at a time. However, mRNA is usually folded up like origami.
Until now, scientists did not understand how the mRNA in bacteria
was unfolded so it could be read by the ribosome.
been known for about 10 years that in humans and other complex
organisms there is a specialized unwinding mechanism that requires
a number of different proteins working in cooperation,”
explained Sean Studer, a chemistry and biochemistry graduate
student who conducted the research. “But the process is
not the same in bacteria, and while there is a great deal of
research on protein synthesis in bacteria, the unfolding step
is one aspect that has been overlooked.”
In order to determine
what factors were needed for the unraveling process to occur,
Joseph and Struder designed a test that used fluorescence to
signal when an mRNA strand unwound. They made mRNA with different
fluorescent molecules attached to either end. When the mRNA
was twisted around on itself, the two fluorescent molecules
were in close proximity and could exchange energy, resulting
in a change in the color of the fluorescence detected. Unfolding
of the mRNA separated the fluorescent molecules and prevented
the color change.
test showed that the mRNA did not unfold when in the presence
of ribosomes alone. Joseph and Studer discovered that unfolding
required a protein called initiation factor 2 as well as initiator
tRNA—a molecule that carries the first amino acid of the
protein described by the mRNA instructions. In addition, the
mRNA must contain a small region, the Shine-Dalgarno sequence,
that allows it to bind to the ribosome. The researchers say
that their study reveals vulnerabilities in bacterial protein
production that can be exploited to design new antibiotics.
“Initiation factor 2, initiator tRNA and the Shine-Dalgarno
sequence are great targets because they are essential to the
unfolding process and they are conserved in bacteria,”
said Joseph. “Since mRNA unfolding in human cells is a
different, more complex process that doesn’t require these
factors, drugs that inactivate them should not harm human cells.”
The researchers say
that the fluorescence test they developed could be a valuable
tool to quickly identify compounds that block the mRNA unfolding
in bacteria and have the potential to be used as antibiotics.
The study was supported
by the National Institutes of Health, the National Science Foundation
and the Human Frontiers Science Program.
Media Contact: Sherry
Seethaler, (858) 534-4656
Joseph, (858) 822-2957