Battling antibioticresistant bacteria
ORNL research showing promise
Oak Ridge National Laboratory scientists’ enzyme research may lead to drugs that will combat antibioticresistant bacteria.
ORNL has found that antibiotics confronting super-resistant bacteria start to selfdestruct before enzymes defending the bacteria even get hold of them.
Scientists Patricia Langan, Kevin Weiss and Leighton Coates have been examining how the enzyme betalactamase makes bacteria resistant to antibiotics.
“There’s a growing problem worldwide of antibiotic resistance,” Langan said. “When we have an infection like meningitis or something similar, we take an antibiotic and that should supposedly kill the bacteria that causes the infection. But there are now some bacteria that can’t be killed by some antibiotics. There are even bacteria that can’t be killed by any antibiotics.”
The beta-lactamase enzyme is one way bacteria such as meningitis and E. coli can become resistant to antibiotics. When antibiotics approach bacterial cells, the enzyme chews them up before they can kill the bacteria.
Around 900 strains of beta-lactamases exist.
Langan, Coates and Weiss have been researching the way the enzyme interacts with Cefotaxime, a strong antibiotic used to treat meningitis and prevent sepsis after abdominal surgery.
“We chose this drug in particular for the study because when bacteria are resistant to a drug that’s really powerful like this, it’s a big deal,” Langan said. “Understanding the reaction is good because then we can replace it with something better.”
To study the reaction between the drug and the enzyme, Weiss worked at a lab within the Center for Structural Molecular Biology to produce a safe strain of E. coli bacteria in a fermenter that looked a lot like a quart of spoiled milk being agitated with an egg beater.
Weiss extracted the beta-lactamase enzyme from the E. coli and the scientists froze the enzyme and the antibiotic at the moment before the enzyme begins to destroy the antibiotic.
“The idea is if we can see exactly how the enzymes break down the antibiotics, we can publish that and people who are doing drug design can design better drugs that don’t catalyze their own destruction.” – PATRICIA LANGAN, ORNL SCIENTIST
They crystallized the reaction and placed it into a small capillary, which was then lowered into Coates’ MaNDi detector at the Spallation Neutron Source.
The MaNDI detector surrounded the sample and used neutrons to show the scientists tiny details in the reaction.
The images showed structural changes occurring in the cell’s active site when the antibiotic begins to bind to the enzyme defending the bacteria. The structural changes jump-started the antibiotic’s breakdown.
“So in a way, the antibiotic is causing its own destruction, which we thought was really interesting,” Langan said.
The scientists are exploring ways to block bacterial enzymes with inhibitors. If medical scientists can put something else in the enzyme’s way to occupy it, then the enzymes can’t break down the antibiotic.
“The idea is if we can see exactly how the enzymes break down the antibiotics, we can publish that and people who are doing drug design can design better drugs that don’t catalyze their own destruction,” Langan said.