Researchers identify key enzyme found in bacteria responsible for heart valve disease

March 5, 2014
This image is an overview of manganese transport and role in providing nucleotide building blocks for DNA. The red, blue and brown shapes are components of the complex that transports manganese into the bacterial cell. NrdEF is the ribonucleotide reductase enzyme that creates the nucleotides and NrdI is the protein required for attaching manganese to the enzyme. Elimination of either NrdEF or NrdI completely prevented Streptococcus sanguinis from causing infective endocarditis. Credit: Todd Kitten, Ph.D.,/ VCU.

A 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 need 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.

This is a false-colored transmission electron micrograph of Streptococcus sanguinis cells (purple ovals) encased within an infected heart valve in an animal model of infective endocarditis. Credit: Todd Kitten, Ph.D.,/ VCU.

"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 . 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 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.

Explore further: How zinc starves lethal bacteria to stop infection

Related Stories

Scientists decode genome of oral pathogen

April 5, 2007

Virginia Commonwealth University researchers have decoded the genome of a bacteria normally present in the healthy human mouth that can cause a deadly heart infection if it enters the bloodstream.

Scientists identify potential key to Lyme disease

February 9, 2009

Researchers at UT Southwestern Medical Center have identified a protein that may help give Lyme disease its bite. The findings suggest that the bacterial protein, which aids in transporting the metal manganese, is essential ...

Recommended for you

New hermit crab uses live coral as its home

September 20, 2017

A new hermit crab species can live in a walking coral's cavity in a reciprocal relationship, replacing the usual marine worm partner, according to a study published September 20, 2017 in the open-access journal PLOS ONE by ...

The right way to repair DNA

September 20, 2017

Is it better to do a task quickly and make mistakes, or to do it slowly but perfectly? When it comes to deciding how to fix breaks in DNA, cells face the same choice between two major repair pathways. The decision matters, ...

Barn owls found to suffer no hearing loss as they age

September 20, 2017

(—A small team of researchers with the University of Oldenburg has found that barn owls do not suffer hearing loss as they get older. In their paper published in Proceedings of the Royal Society B, the group describes ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.