A team led by Johns Hopkins researchers has solved
important puzzles concerning how certain
proteins guide the reproduction of bacteria, discoveries
that could lead to a new type of antibiotics.
In a recent study published in the journal Current
Biology, the scientists reported how a
beltlike structure called a Z ring, which pinches a
rod-shaped bacterium to produce two offspring, can
be disabled by a protein called MinC. By exploiting this
vulnerability, the researchers said,
pharmaceutical companies may find a way to fight infections
that no longer respond to older
medications.
"The potential medical applications of our discovery
are significant," said Alex Dajkovic, lead
author of the paper. "Because the molecules involved in
cell division are very similar in almost all
bacteria, the process we uncovered provides a new target
for the people who make antibiotics. This is
extremely important because antibiotic resistance is on the
rise, and many preventable deaths,
especially in the developing world, are caused by bacterial
infections."
Dajkovic helped make the discoveries as a postdoctoral
fellow in the lab of Denis Wirtz, a
professor of chemical
and biomolecular engineering in the Whiting School of
Engineering. Dajkovic is
now a researcher at Institut Curie in Paris.
Denis Wirtz
|
Wirtz, who also is associate director of the Johns
Hopkins Institute for NanoBioTechnology,
noted that "most antibiotics target the ability of bacteria
to build their cell walls or their ability to
make proteins or DNA. With this paper, Alex and the rest of
the team identified new molecular
targets that could disrupt bacterial cell division. If the
bacteria can't reproduce, the infection will
die."
The researchers focused on the rod-shaped bacterium E.
coli, commonly found in the human
digestive tract, which serves as a model organism for study
of basic bacterial processes. When these
single-celled microbes want to multiply, a structure called
the Z ring forms, then begins to tighten like
a rubber band around each bacterium's midsection. The Z
ring helps to pinch the rod-shaped body into
two microbial sausages that finally split apart to form two
cells.
For about 20 years, researchers have known about the Z
ring but have not understood precisely
how it operated and why it always formed in the middle of
rod-shaped cells. The main components of Z
rings are filaments of a protein molecule called FtsZ.
In the new journal article, the Johns Hopkins-led
researchers were able to report for the first
time that the changing of FtsZ threads from a liquidlike
form to a more solid structure inside the cell
is important for the formation of the Z ring. The team
found that FtsZ threads weave themselves
into a framework or scaffold that can hold all the other
molecules involved in the cell division process.
The FtsZ filaments are able to weave this tapestry, the
researchers learned, because they tend to
attract one another and interact along the length of each
thread.
The team also discovered that MinC, another protein
inside the bacterial cell, disrupts this
process by liquefying the structure that is used to form a
Z ring. "MinC blocks the attraction between
FtsZ filaments along their lengths, and it also makes the
filaments more fragile," Dajkovic said. "This
has the effect of shearing the weavings in the tapestry of
the Z ring, which causes the whole
structure to fall apart."
MinC is most prevalent on the outer ends of the
rod-shaped bacterial cell, the researchers said,
and this explains why the Z ring always forms and splits
the cell in the middle, where it is less likely to
encounter its protein foe. The team members said this
discovery also presents a promising
opportunity: A new drug that mimics the effects of MinC
could play havoc with the bacterial
reproductive process and thereby put an end to an
infection.
The findings resulted from a collaboration involving
Dajkovic, whose background is in cell biology
and biochemistry; Wirtz, whose expertise is in biophysics
and engineering; and Sean X. Sun,
a Johns
Hopkins assistant professor of mechanical engineering
who provided computational modeling of the cell
division process. Wirtz and Sun were co-authors of the
Current Biology paper, along with Ganhui Lan, a
doctoral student in Sun's lab, and Joe Lutkenhaus, a
University Distinguished Professor in the
Department of Microbiology, Molecular Genetics and
Immunology at the University of Kansas Medical
Center. Lutkenhaus was Dajkovic's faculty adviser as a
doctoral student.
The research was supported by grants from the National
Institutes of Health.
