Resisting Resistance:
LSU-CAMD’s Ongoing Battle to Keep Antibiotics Working
by Ashley Berthelot, Research Editor at LSU Public Affairs
Since the discovery of penicillin in 1928, the world has breathed a collective sigh of relief. Bacterial infections, once a slow and painful death sentence, could now be eradicated by something as simple as a small pill. It seemed that modern medicine had saved the day. But only four years after penicillin entered mass production, something strange happened. Staphylococcus aureus, more commonly known as staph, developed a resistance to the antibiotic. Other bacteria soon followed suit. Fast forward to today, and the problem has grown tremendously, threatening the efficacy of the drugs we depend on.
A general overuse of antibiotics has led to a dramatic increase in the growth of drug-resistant bacteria. The improper usage of these medications only fuels the already rapid spread of the problem. “We’re definitely seeing more resistant staph bacteria because of previous exposure to antibiotics,” said Dr. Waref Azmeh, an infectious disease specialist in Baton Rouge.
According to Dr. Azmeh, part of the issue is that patients are often capable of pressuring their physicians into prescribing antibiotics, even when the illness in question is viral and therefore not responsive to such medication. “Most viral infections get better on their own within three to four days and then the patient attributes that to the antibiotics. But it’s not so,” said Azmeh. “But patients expect a prescription, and it makes doctors feel like they’re doing something. And, often, once you have a bad habit, it sticks.”
Pharmaceutical companies are also partly to blame, as they diligently work to develop a constant barrage of new strategies for marketing antibiotics to physicians. “They’re getting smarter and smarter. They really know how to keep a product in your face constantly,” said Dr. Azmeh.
Several national health organizations, including the Infectious Diseases Society of America (IDSA), the Centers for Disease Control (CDC) and the Food and Drug Administration (FDA), among others, are engaged in long-term campaigns to educate the public about the dangers of improper antibiotic usage. But the numbers of resistant- bacteria continue to grow, and many scientists agree that we are perched on the brink of a world-wide health crisis.
In 1974, 2% of staph bacteria showed resistance to antibiotics. That number jumped to 22% in 1995. Today we’re facing the astronomical figure of more than 60% of staph that are currently resistant to all forms of antibiotics except for one. And that last antibiotic is near-toxic and can cause serious side effects.
“It’s not a question of if, but when bacteria become completely resistant to existing antibiotics,” said Grover Waldrop, associate professor of biological sciences at LSU. “It’s happening as we speak. We are witnessing evolution in real-time.”
“It’s a significant problem,” agreed Azmeh. “For example, if staph is not treated within a few days, it can kill.”
Waldrop is currently waging war against these virulent strains of bacteria with the help of Pfizer Pharmaceuticals and LSU’s Center for Advanced Microstructures and Devices (CAMD). As the only source of synchrotron radiation in the south, CAMD plays a pivotal role in providing Waldrop with the extremely intense X-rays necessary to design molecules that will inhibit resistance in bacteria. With luck, the molecules Waldrop is developing may be produced and distributed clinically to use as antibiotics that are essentially immune to bacterial resistance.
Basically, antibiotics work by targeting and destroying essential enzymes in the invading bacteria. Waldrop’s research focuses on the inhibition of a particularly important enzyme called acetyl-CoA carboxylase (ACC), which is required to support bacterial growth.
Left: Carboxyltransferase crystals; Center: Zn ribbon motif of carboxyltransferase; Right: Staphylococcus aureus carboxyltransferase.
In order to find molecules that will bind and inhibit ACC, one must have an excruciatingly thorough knowledge of the three-dimensional structure of the enzyme. This approach, commonly known as structure-based design, is best understood through a simple analogy. “If the structure of the inside of a lock was understood in detail, then a key could be designed and manufactured to fit the lock,” said Waldrop. “In the case of enzymes, once the structure is known, a molecule that binds to it and prevents it from functioning can be designed and synthesized.”
The only way to determine these three-dimensional structures is through a process called X-ray crystallography, which is entirely dependent upon having access to the CAMD synchrotron’s high-intensity X-rays. Because of this technology, Waldrop has already successfully determined the structure of ACC from several pathogenic bacteria, including staph. “It’s only a step,” cautioned Waldrop, but it does bring them incrementally closer to finding a solution for this growing problem.
Drug discovery takes a minimum of 5-10 years and costs an average of $500 million per drug. Because of the lag time between research and realization, it’s that much more important to support studies like Waldrop’s right now. However, according to Dr. Azmeh, pharmaceutical companies find little incentive in investing in antibiotic discovery. “A new antibiotic will most likely lose efficacy in 10-15 years. This is not a good investment. Bacteria are living organisms – they adapt.”
Azmeh says we are currently trapped in a situation where we’re trying to get as much life as possible from a single drug before significant levels of resistance occur. “If no new drugs were to be developed in the next five to ten years, the antibiotics we have now will lose effectiveness,” he said. “We will go back to the pre-antibiotic era, a time when infectious diseases were the number one killer in the population.”
For now, Waldrop is back in the lab, working hard to identify more ACC structures. “It’s not an exaggeration to say that we could not have succeeded to this point without CAMD. They’re playing a vital role in battling one of the most pressing health care problems currently facing our society.” And he’ll continue to work on the problem with CAMD and Pfizer as long as the pharmaceuticals company continues its support. “You can’t wait until the problem actually becomes an epidemic before you do something. Once it reaches that point,” he said, “it’s just too late.”
