The
discovery, made possible through a revolutionary method used to color bacterial
cell walls developed at IU, is an important step forward in research on
bacterial growth and could inform efforts to develop drugs that combat
antibiotic-resistant bacteria.
Globally,
antibiotic-resistant bacteria, or "superbugs," pose a major risk to
human health. The World Health Organization estimates about 480,000 people
develop multi-drug resistant tuberculosis each year. In the U.S., the Centers
for Disease Control estimates 1 in 4 hospital-acquired infections in long-term
patients are caused by six major strains of the bugs.
"This
is the first study to 'connect the dots' between each part of the cell involved
in bacterial cellular division," said Yves Brun, the Clyde Culbertson
Professor of Biology in the IU Bloomington College of Arts and Sciences'
Department of Biology, who is an author on the study. "We've finally
closed the circle on this mechanism and opened the door to more precise methods
in the fight against antibiotic-resistant bacteria.
"If
you understand how an engine works, you can shut it down by removing a single
part," Brun said. "You no longer need to throw a hammer into the
works to destroy it."
Early
antibiotics like penicillin function like a hammer: a blunt instrument that
destroys the bacterial cell in the midst of division by tricking cell
wall-making enzymes called penicillin-binding proteins, or PBPs, into binding
to the drug rather than the building blocks of the cell walls, causing the
walls to breach and the cells to explode.
Other
parts of the cell that drive bacterial division include cytoskeletal proteins,
called FtsA and FtsZ, which form skeleton-like fibers inside cells to direct
construction of the cell wall. All three elements must coordinate to build a
cell wall in the middle of the cell to ensure the material inside doesn't
escape after it splits in half.
The
fact that these three parts of the cell play a role in cellular division is
known, but the new study is the first to show exactly how they coordinate.
Essentially, Brun said, FtsZ acts as a "foreman" that directs the
movement of PBP "workers" as they construct a cell wall.
The
researchers were able to detect the action with high-tech, multi-colored dyes
called fluorescent D-amino acids, or FDAAs, discovered five years ago in the
lab of Michael VanNieuwenhze, professor in the IU Bloomington College of Arts
and Sciences' Department of Chemistry, who is a co-author on the study.
"The
application of different colors of these dyes during the cell wall construction
process revealed a 'bull's-eye pattern,' indicating the circular wall is built
from the outer edge of the cell inward to the center," VanNieuwenhze said.
The
study also solves another mystery: How do FtsZ molecules build the wall? The
researchers found that FtsZ -- which is arrayed in a biochemical chain called a
filament -- constantly loses a molecule at one end and gains a molecule at the
other end, resulting in a circular motion around the cell's edge described as
"treadmilling."
IU
researchers chemically labeled the cells for analysis. Harvard scientists
performed the experiments that showed the motion of the FtsZ and PBP proteins
inside the cell.
The
subject of a U.S. patent filed by the IU Research and Technology Corp., FDAA
dyes have played an important part in dozens of other scientific papers on
bacteria since 2012. VanNieuwenhze's lab also has about 50 material transfer
agreements with researchers across the globe to provide access to the tool.
The
creation of the dyes at IU was led by Erkin Kuru, a former Ph.D. student in the
labs of VanNieuwenhze and Brun who is currently a research fellow at Harvard.
Kuru and Yen-Pang Hsu, a IU Ph.D. student also in the labs of VanNieuwenhze and
Brun, are co-authors on the study.
"This
is the first time we've been able to observe cell division as a dynamic process
-- that is, a process occurring over time," Kuru said. "This wasn't
possible before since we lacked the tools to see it."
Hsu
added that "the visualization of these cell structures is no small task
when you consider the organism that contains them is less than a micrometer --
or one-thousand of a millimeter -- wide. We wouldn't have been able to measure
the fluorescent patterns in these cells without the technology at the IU Light
Microscopy Imaging Center."
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Posted by Dr. Tim Sandle
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Pharmaceutical Microbiology