CINCINNATI—Researchers at the University of Cincinnati (UC) report
that they have solved the crystal structure of a protein involved in holding
bacterial cells together in a biofilm, a major development in their exploration
of the causes of hospital-acquired infections.
The finding, the researchers say, enables them to have an
atomic-level view of what the protein looks like and how it becomes "sticky” in
the presence of zinc ions, forming an extensive adhesive contact crucial to the
formation of infection-causing biofilms.
The researchers report their findings in the online Early
Edition of PNAS, the official journal
of the National Academy of Sciences. Andrew Herr, PhD, an associate professor
in the department of molecular genetics, biochemistry and microbiology at UC and
Ohio Eminent Scholar in structural biology, led the research and wrote the
The research team, in addition to Herr, consisted of Deborah
Conrady, PhD, now a postdoctoral fellow at the University of British Columbia,
and Jeffrey Wilson, PhD, a former postdoctoral fellow at UC.
"Understanding the mechanisms of biofilm formation will
allow us to combat the significant pathogenic advantages of biofilm-based
infectious diseases,” says Herr.
Hospital-acquired infections affect about 1.7 million people
per year in the United States and result in an estimated 99,000 deaths
annually, according to the Centers for Disease Control and Prevention. About
two-thirds of all hospital-acquired infections can be traced to two staphylococcal
species, Staphylococcus aureus—including
methicillin-resistant strains (MRSA) that are particularly difficult to
Staphylococci can grow as biofilms, which are specialized
communities of bacteria that are highly resistant to antibiotics and immune
responses. They are remarkably adhesive and can grow on many surfaces,
including implanted medical devices such as pacemakers, heart valve
replacements and artificial joints. Preventing or inhibiting the growth of such
biofilms would dramatically reduce the incidence of staph infections.
Previously, researchers in Herr’s lab had detailed findings that
the presence of zinc is crucial to the formation of infection-causing biofilms.
Zinc, they found, causes a protein on the bacterial surface to act like
molecular Velcro, allowing the bacterial cells in the biofilm to stick to one
another. Zinc chelation, a way to make the zinc unavailable to the bacteria,
prevented biofilm formation by Staphylococcus
epidermidis and Staphylococcus
In the new research, the investigators determined the atomic
structure of a portion of an adhesive protein Aap bound to zinc by growing
crystals of the protein, freezing them in liquid nitrogen and bombarding them
with highly intense X-rays. They then measured how the X-rays were scattered by
the crystal, and used those measurements to determine the 3D position of the
atoms in the protein.
The protein, the researchers found, adopts an elongated
flexible fold with zinc ions bridging two protein chains. The mode of assembly indicates that Aap is
likely to form twisted rope-like structures between bacterial cells.
"We can see literally what the structure of the protein is,”
Herr says. "In other words, how it is put together, how it folds back on itself
to form its unique shape and how two copies of the protein latch onto the zinc
ion and stick together like molecular Velcro.”
Knowing the structure allows researchers to understand which
parts of the protein to target therapeutically, Herr says, which could provide
new approaches for disrupting the formation of biofilms. The most practical applications might involve
coatings for implanted medical devices, or rinses that a surgeon could use to
clear the area around an implant.
The research project was supported by the National
Institutes of Health and by a pilot grant from UC’s Midwest Center for Emerging
Infectious Diseases; Herr also had access to funds from the State of Ohio
Eminent Scholars Program. The authors report no conflicts of interest.