It’s not nice to fool Mother Nature, but Dr. Hung-Wen (Ben) Liu has been trying for more than 20 years to do just that.
When Liu began his battle against the old enemy of drug-resistant diseases, he learned that as a chemist Mother Nature is good, really good.
Just four years after drug companies started mass-production of penicillin in 1943, microbes that could resist it began surfacing, says the professor of pharmacy at The University of Texas at Austin. Finding an antibiotic that can fight the big fight has become so crucial to public health that the officials at the World Health Organization and the U.S. Centers for Disease Control and Prevention are calling upon scientists and funding organizations to take the threat seriously.
“The threat U.S. officials fear is that we could be plunged back into a pre-antibiotic era as microorganisms become increasingly immune to our current disease-fighting arsenal of drugs,” said Liu, who holds the George H. Hitchings Regents Chair in Drug Design in the College of Pharmacy.
In their medicinal chemistry laboratory, Liu and 23 enthusiastic graduate and postdoctoral students configure and replicate models—Mother Nature’s models, that is—trying to develop weapons to use against antibiotic-resistant bacteria.
The National Institutes of Health is funding his research through multiple four-year grants totaling $3.5 million. He and his team are attempting to generate new antibiotics by genetically changing the original antibiotic-producing bacteria strain, thereby creating a library of novel chemical entities.
“These hybrid compounds with potentially new or improved antibiotic activity will be useful in overcoming the bacteria’s resistance,” Liu said.
“There are many interesting and amazing things to learn when you study biological systems, especially proteins which have catalytic activity,” Liu said. “Our challenge is to use what we learn to develop a strategy to control or mimic the natural bioprocesses.
Dr. Liu works with a team of enthusiastic graduate and postdoctoral students. Pictured here (from left to right) are Chad Melancon III, Jeff Munos, Dr. Liu, Chris Thibodeaux, Jess White, Dr. Haruko Takahashi, Dr. Kenji Itoh and Dr. Yung-nan Liu.
“You can always learn a lesson from Mother Nature,” Liu said.
“Antibiotics save lives, but we have taken them for granted. We have had decades and decades of misuse and overuse that has led to many new strains of resistant bacteria—leaving the general population unprotected in some cases. If current medicine cannot kill bacteria—we’re back to the Dark Ages.”
The standard of living, of course, is higher today and the death rate may not be as high, “but if one deadly bacteria develops a drug resistance there could be a chain of events and other bacteria will develop resistance,” Liu said.
Already, thousands of hospital patients die every year of bacterial infections that are resistant to the current regimen of antibiotics.
So, if you are one of those people who leave a doctor’s office asking, “But wait. Where are my antibiotics?” Liu is talking about you.
Unfortunately, he is talking about way too many people—those who rush to the doctor demanding antibiotics for everything from the sniffles to a stomachache.
If you need help breaking the antibiotic habit, here’s an easy checklist:
- Bacterial infections such as pneumonia, pink eye, meningitis, cystitis, ear infections, abscess, lyme disease, leprosy and tuberculosis CAN all be treated by antibiotics.
- The common cold and the flu are caused by viruses and CANNOT be treated by antibiotics. Or, as the Centers for Disease Control and Prevention says in a public leaflet, “Cold or flu, antibiotics don’t work for you.”
One of the most recent worries in public health is the increase of Staphylococcal infections that withstand the usual drugs. Staph bacteria spread mostly through direct contact with infected people, but also through contact with contaminated surfaces, such as towels and wound dressings. A staph infection can turn deadly.
“Tetracycline is commonly used, but if it doesn’t work then you have to keep trying different classes of drugs until you find one that works,” Liu said.
Graduate student Svetlana Borisova, who has been with Liu’s research group for six years, said one of their directions is the study of biosynthesis of antibiotics produced by the Streptomyces strains like fosfomycin, tylosin, kijanomycin, methymycin and pikromycin. The researchers use genetic engineering to create new antibiotics.
“We haven’t found any new compounds with improved biological activity,” said Borisova. “But this is only the beginning and a few promising compounds have been created.
“Resistance mechanisms developed by pathogens are often quite similar to the self-resistance mechanisms of antibiotic producers. Therefore, knowing more about self-resistance will be helpful for the understanding of the pathogen resistance.”
In their strategy to develop new antibiotics, Liu and his team try to modify the sugar component of existing antibiotics. The major thrust of the research lies at the crossroads of chemistry and biology—the interdisciplinary work involving the areas not only of pharmacy but molecular biology, chemistry and biochemistry.
“Bacteria are pretty smart,” Liu said. “We will always have to come out with new strategies because there will never be a drug that lasts forever. The challenge is we have to continue to learn better ways to fight.”
Dr. Liu encourages graduate student Zhihau Tao as she works on the development of a therapeutic agent.
Liu came to the College of Pharmacy from the University of Minnesota. He received his Ph.D. from Columbia University and did his postdoctorate work at the Massachusetts Institute of Technology.
While growing up in Taiwan, Liu was interested in chemistry and how nature works.
“I constantly wondered why does a flower have this color or why does an apple have a specific taste and smell,” he said. “What kind of chemistry is responsible for that, I asked myself.”
He also used to build model airplanes, configuring miniature pieces into perfect replicas of real aircraft. Through cautious construction, he could understand the mechanics of a large plane, replicate it and even alter the model to suit his purposes.
Liu now uses genes and enzymes as his modeling components. In their research, Liu and his graduate students manipulate an organism’s biosynthetic machinery at the genetic level to generate new molecules.
“We alter the structure of a natural product and try and generate new or improved activity,” he said.
Basically, they can turn off specific genes, shuffle genes with others, construct hybrid gene clusters and create new compounds.
Graduate student Chad Melancon III has worked in the Liu lab for three years and says antibiotics need to be constantly developed.
“Hopefully,” he said, “resistant bacteria that are immune to currently available antibiotics have never encountered these new compounds before—their mode of resistance may not work, leaving them vulnerable.”
No antibiotic can remain as effective as it was when it was first introduced, said Chad Melancon, a biochemistry graduate student who has worked in the Liu lab for three years.
“As a result,” he said, “new antibiotics need to be constantly developed in order to have some that are effective against resistant strains.”
Liu is trying to develop methods for creating large numbers of active antibiotic derivatives quickly and easily so that we have many new weapons against antibiotic resistant bacterial pathogens before they are actually needed.”
The vast majority of antibiotics used today are actually natural products isolated from bacteria,” Melancon said. “These bacteria (many from the family Actinomycetes) are the ‘good ones’ because they make the antibiotics we use to fight the ‘bad’ pathogenic bacteria.”
The researchers are concentrating on scaling up and streamlining genetic engineering efforts to make a large collection of mutant strains that will help create many new antibiotic analogues.
“Even the most sophisticated radar systems are useless without an arsenal of weapons to back them up,” said Liu.
Office of Public Affairs/College of Pharmacy
Photos: Sherre Paris