Disease-causing bacterium found in the mouth needs manganese, a trace
mineral, in order to cause a serious heart infection, according to a
preclinical study led by researchers at Virginia Commonwealth University
Philips Institute for Oral Health Research in the School of Dentistry.
The findings, which may solve a longstanding mystery of why some
bacteria need manganese to cause disease, provide possible new targets for
antibiotics.
Researchers from VCU and MIT have been studying the bacterium
Streptococcus sanguinis, which lives in the mouth, to understand
its role in infective endocarditis, a heart valve disease. The infection is
hard to treat and can be deadly -- killing more than 20 percent of the people
who contract it.
Researchers have known for some time that several types of bacteria
responsible for serious infections -- including S. sanguinis -- need more
manganese than others to grow normally.
In joint studies published this week in the Journal of
Biological Chemistry, researchers showed that an enzyme that provides the
building blocks needed for making DNA requires manganese to do its job. When
the VCU team eliminated that enzyme or a second protein that attaches the
manganese to the enzyme, then the bacterium could no longer cause endocarditis,
nor survive within the animal model. The MIT team carefully examined the
activity of the purified enzymes and determined the function of each. The
VCU-MIT study is the first of its kind to test the importance of these enzymes
for causing any disease.
Understanding the importance of manganese in the cell has been key to
learning the best way to target the bacterium and stop it from causing disease,
according to corresponding author Todd Kitten, Ph.D., associate professor at
the Phillips Institute for Oral Health Research at the VCU School of Dentistry.
"The best antibiotics attack parts of a bacterium that are critical
for bacterial survival, but are not found in human cells," Kitten said.
"The manganese-requiring enzyme meets both requirements because
these bacteria need it to survive and humans use a very different,
iron-containing enzyme to make DNA building blocks. It is the manganese
requirement that makes the bacterial proteins good targets," he said.
Kitten added that humans have very little manganese in their bodies, so
these bacteria require specialized systems to take in enough manganese to
survive. These uptake systems are not found in humans. The team is in the early
stages of a collaboration with Glen Kellogg, Ph.D., associate professor in the
Department of Medicinal Chemistry at the VCU School of Pharmacy, to create
designer drugs to attack the manganese uptake system in these bacteria.
Down the road, it could be possible to target several other
disease-causing bacteria that also have this enzyme and likely need it to cause
disease, including MRSA; the flesh-eating bacterium, Streptococcus pyogenes;
and the bacterium that causes anthrax.
The team is also examining whether manganese has other activities in
these bacteria that might be equally important.
The research builds on the previously published reports of other VCU
researchers. A 1995 study published in Infection and Immunity led by Francis
Macrina, Ph.D., currently vice president for research at VCU, showed for the
first time that a protein that turned out to be a manganese uptake protein was
necessary for causing disease.
In the years since, dozens of researchers have discovered similar
proteins in other disease-causing bacteria. This study also builds on work done
by a collaborative VCU group that was the first to determine the DNA sequence
of S. sanguinis.
Story Source:
The above story is based on materials provided by Virginia
Commonwealth University. The original article was written by
Sathya Achia Abraham. Note: Materials may be edited for content and
length.
Journal References:
D. V. Rhodes, K. E. Crump, O. Makhlynets, M. Snyder, X. Ge, P. Xu, J.
Stubbe, T. Kitten. Genetic Characterization and Role in Virulence of
the Ribonucleotide Reductases of Streptococcus sanguinis. Journal
of Biological Chemistry, 2013; 289 (9): 6273 DOI: 10.1074/jbc.M113.533620
O. Makhlynets, A. K. Boal, D. V. Rhodes, T. Kitten, A. C. Rosenzweig, J.
Stubbe.Streptococcus sanguinis Class Ib Ribonucleotide Reductase: HIGH
ACTIVITY WITH BOTH IRON AND MANGANESE COFACTORS AND STRUCTURAL INSIGHTS. Journal
of Biological Chemistry, 2013; 289 (9): 6259 DOI:10.1074/jbc.M113.533554
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