Vanderbilt studies outline new model for staph bone infections

August 1, 2013, Vanderbilt University Medical Center

Osteomyelitis, a debilitating bone infection most frequently caused by Staphylococcus aureus ("staph") bacteria, is particularly challenging to treat.

Now, Vanderbilt microbiologist Eric Skaar, Ph.D., MPH, and colleagues have identified a staph-killing compound that may be an effective treatment for osteomyelitis, and they have developed a new that will be useful for testing this compound and for generating additional .

James Cassat, M.D., Ph.D., a fellow in Pediatric Infectious Diseases who is interested in improving treatments for children with bone infections, led the mouse model studies. Working with colleagues in the Vanderbilt Center for Bone Biology and the Vanderbilt University Institute of Imaging Science, Cassat developed micro-computed tomography (micro-CT) imaging technologies to visualize a surgically introduced in progress.

"The micro-CT gives excellent resolution images of the damage that's being done to the bone," said Skaar, the Ernest W. Goodpasture Professor of Pathology. "We found that staph is not only destroying bone, but it's also promoting new bone growth. Staph is causing profound changes in ."

Cassat also established methods for recovering—and counting—bacteria from the infected bone.

"We're not aware of any other bone infection models where you can pull the bacteria out of a bone and count them in a highly reproducible manner," Skaar said. "From a therapeutic development standpoint, we think this model is going to allow investigators to test new compounds for efficacy against bone infections caused by staph or any other bacteria that cause osteomyelitis."

Several pharmaceutical companies have already approached Skaar and his team about testing compounds in the new bone infection model, which the investigators describe in the June 12 issue of Cell Host & Microbe.

Using the model, the team demonstrated that a certain protein secreted by staph plays a critical role in the pathogenesis of osteomyelitis. Understanding the specific bacterial factors—and the bone cell signals—that promote bone destruction and formation during infection could lead to new strategies for restoring bone balance, Skaar said.

"Even if it's not possible to kill the bacteria, compounds that manipulate bone growth or destruction might have some therapeutic benefit."

Still, Skaar is interested in treatments that will eliminate the infection.

The staph bacteria involved in osteomyelitis and in other persistent infections (such as lung infections in cystic fibrosis) are often a sub-class of staph known as "small colony variants." These staph variants grow slowly and are resistant to entire classes of antibiotics commonly used to treat bone and lung infections, Skaar said.

One way that staph bacteria become antibiotic-resistant small colony variants is by changing the way they generate energy. Instead of using respiration, they switch to fermentation, which blocks antibiotic entry and slows bacterial growth.

In a high-throughput screen for compounds that activate a heme-sensing bacterial pathway, graduate student Laura Mike identified a compound that kills fermenting staph. The findings are reported in a recent issue of the Proceedings of the National Academy of Sciences.

"This is a completely new molecular activity," Skaar said. "We don't know of other molecules that are toxic against fermenting bacteria."

The compound—and derivatives synthesized by Gary Sulikowski, Ph.D., and his team—might be useful in treating staph small colony variants, or in preventing their emergence.

The investigators demonstrated in culture that treating staph with the antibiotic gentamicin forced it to become a small colony variant and ferment, and that co-treatment with the new compound prevented resistance and killed all of the bacteria.

"We think a really interesting therapeutic strategy for this compound is that it might augment the antimicrobial activity of existing classes of antibiotics by preventing resistance to them—it might extend the lifetime of these classes of antibiotics," Skaar said.

This would be similar to the drug Augmentin, which combines a traditional penicillin-type antibiotic and a compound that blocks bacterial resistance.

The investigators are excited to test the new compound in the mouse model of osteomyelitis. First, they will treat the mice with gentamicin and assess whether small colony variants form. If so, they will co-administer the new compound to test if it prevents resistance, and they will also assess it as a single treatment for the persistent infection.

Skaar stressed that Vanderbilt's collaborative environment made these studies possible. Daniel Perrien, Ph.D., and Florent Elefteriou, Ph.D., in the Vanderbilt Center for Bone Biology and colleagues in the Vanderbilt University Institute of Imaging Science were critical in facilitating development of the infection model. Sulikowski and other colleagues in the Vanderbilt Institute of Chemical Biology (VICB) enabled the compound development.

"This is exactly the kind of work the VICB is promoting – getting biologists like me together with chemists, to make new therapeutics," Skaar said.

Explore further: A new model—and possible treatment—for staph bone infections

Related Stories

A new model—and possible treatment—for staph bone infections

June 19, 2013
Osteomyelitis – a debilitating bone infection most frequently caused by Staphylococcus aureus ("staph") bacteria – is particularly challenging to treat.

Workers at industrial farms carry drug-resistant bacteria associated with livestock

July 2, 2013
A new study found drug-resistant bacteria associated with livestock in the noses of industrial livestock workers in North Carolina but not in the noses of antibiotic-free livestock workers. The drug-resistant bacteria examined ...

New compound overcomes drug-resistant Staph infection in mice

January 7, 2013
Researchers have discovered a new compound that restores the health of mice infected with methicillin-resistant Staphylococcus aureus (MRSA), an otherwise dangerous bacterial infection. The new compound targets an enzyme ...

Recommended for you

Forces from fluid in the developing lung play an essential role in organ development

January 23, 2018
It is a marvel of nature: during gestation, multiple tissue types cooperate in building the elegantly functional structures of organs, from the brain's folds to the heart's multiple chambers. A recent study by Princeton researchers ...

More surprises about blood development—and a possible lead for making lymphocytes

January 22, 2018
Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we are born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists ...

How metal scaffolds enhance the bone healing process

January 22, 2018
A new study shows how mechanically optimized constructs known as titanium-mesh scaffolds can optimize bone regeneration. The induction of bone regeneration is of importance when treating large bone defects. As demonstrated ...

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

0 comments

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.