Structure discovered for promising tuberculosis drug target

Oct 25, 2012
This is a 3-D model of the outside surface of the enzyme that helps M. tuberculosis bacteria resist common antibiotics. Blue indicates positively charged atoms; red indicates negatively charged atoms. A peptidoglycan (green) is bound inside the enzyme’s active site. Credit: Mario A. Bianchet

Researchers at Johns Hopkins have figured out the three-dimensional shape of the protein responsible for creating unique bonds within the cell wall of the bacteria that cause tuberculosis. The bonds make the bacteria resistant to currently available drug therapies, contributing to the alarming rise of these super-bacteria throughout the world.

With the in hand, the scientists say, designers have a clear way forward for weakening the and killing these . Their results are reported in a paper published online Oct. 25 in Structure.

"We've known for a while that this protein would make a good , but without a structural model, drug discovery is like blindly choosing random objects to fit into a small hole of unknown shape and size. The results of our study have removed the blindfold," says L. Mario Amzel, Ph.D., professor and director of the Department of Biophysics and at The Johns Hopkins University School of Medicine.

The Johns Hopkins team used a technique called X-ray crystallography to scatter radiation off a specially prepared portion of the enzyme that forms the unique molecular bonds within the cell wall of Mycobacterium tuberculosis. They then used information about the direction and intensity of the radiation scattered to build a 3-D model of the arrangement of atoms in the enzyme.

Mario A. Bianchet, Ph.D., assistant professor of neurology at Johns Hopkins and a member of the research team, says the challenge of is that most of the long and costly standard drug treatment is just to get rid of the roughly 1 percent of bacteria that persist after the first week of a patient's treatment. "The 'persisters' resist in part because of unique bonds within their cell walls. Their cell walls form a thick, three-layered boundary between the bacteria and the outside world, including a middle layer of interlocking molecules, called peptidoglycans, that form a network resembling a chain-link fence," says Bianchet.

Peptidoglycans are long chains of individual sugar molecules with short protein branches extending from every other sugar on alternating sides of the chain. Specific enzymes bond the protein branches to each other to create a meshwork. In most species of bacteria, Amzel says, the majority of the bonds between these branches are created between position 4 on one branch and position 3 on an opposing branch. In M. tuberculosis, however, the majority of the bonds are created between positions 3 on both branches. The most common antibiotics interfere with the enzyme that creates the 4-3 bonds, which is enough to destabilize the cell wall and kill most of the TB bacteria.

The bacteria that persist have a particularly high level of 3-3 bonds between the peptidoglycan chains in their cell walls. These 3-3 bonds are created by a different enzyme, the one that Amzel and Bianchet studied, which is not specifically targeted by any current drugs. In addition to showing the structure of the enzyme, the team also showed a peptidoglycan molecule inside the action site where the 3-3 bonds are made, giving drug designers even more details about the way the protein works.

Amzel adds that "beyond fighting TB, the structure of this enzyme may help us fight other disease-causing that have similar enzymes, such as Enterococcus faecium and the spore-forming, drug-resistant Clostridium difficile."

Explore further: 'K-to-M' histone mutations: How repressing the repressors may drive tissue-specific cancers

More information: Structure doi: 10.1016/j.str.2012.09.016

add to favorites email to friend print save as pdf

Related Stories

Energy-saving bacteria resist antibiotics

Sep 03, 2008

Bacteria save energy by producing proteins that moonlight, having different roles at different times, which may also protect the microbes from being killed. The moonlighting activity of one enzyme from the tuberculosis bacterium ...

Johns Hopkins team finds new way to attack TB (w/ Video)

Mar 24, 2010

Suspecting that a particular protein in tuberculosis was likely to be vital to the bacteria's survival, Johns Hopkins scientists screened 175,000 small chemical compounds and identified a potent class of compounds that selectively ...

Structural study of anthrax yields new antibiotic target

Jan 28, 2008

Researchers studying anthrax knew they were onto something when they discovered an opponent the bacterium couldn’t outwit. Probing a bit deeper, they discovered this was because the attacker was interacting ...

Recommended for you

New tool aids stem cell engineering for medical research

Aug 28, 2014

A Mayo Clinic researcher and his collaborators have developed an online analytic tool that will speed up and enhance the process of re-engineering cells for biomedical investigation. CellNet is a free-use Internet platform ...

User comments : 0