Current research by two Bradley professors could prove critical to a war in which victory was prematurely declared.
“The war against infectious disease has been won,” proclaimed U.S. Surgeon General William H. Stewart in 1969. One of humankind’s greatest achievements, the eradication of infectious disease meant no more needless deaths from the likes of smallpox, malaria or polio. But there was just one problem: he was dead-wrong.
Produced in mass quantities, antibiotics were hailed as a “miracle cure” that would forever put an end to this threat. And they were extraordinarily successful—so successful, that by the 1980s, drug makers had slowed efforts to develop new antibiotics, if not stopped them all together.
But as early as the 1950s, there had been signs of bacterial resistance to these miracle drugs, and since the Surgeon General made his infamous remarks, drug-resistant bacteria have exploded. Diseases like tuberculosis, once thought to be relics of the past, have re-emerged, while pneumonia, malaria, hepatitis and staph infections continue to claim tens of thousands of lives each year.
Meanwhile, FDA approval of new antibiotics has slowed to a trickle. Between 1983 and 1987, 16 new antibiotics were approved by the Food and Drug Administration; two decades later, just four were approved in the five years between 2003 and 2007. Considering the life-and-death implications, the research of Bradley professors Dr. Brad Andersh and Dr. Keith Johnson is not only significant, it could help pave the way to a new generation of antibiotics.
The Hands of Activity
“Since I’ve been at Bradley, I’ve worked on a host of different research problems…with well over 40 students. Relatively recently, we’ve been tackling this issue of the lack of new antibiotics coming through the pipeline,” says Dr. Andersh, associate professor of organic chemistry. Working in collaboration with Dr. Johnson, his colleague in the biology department, Andersh and his team of student researchers didn’t set out with this goal in mind—like a lot of scientific research, it developed out of another project.
“We had developed a very unique method of making a certain group of compounds,” he explains, “and found evidence that structurally related compounds have some analgesic activity, similar to ibuprofen or acetaminophen. As we looked in the literature, we found reports of people testing these compounds for antifungal and antiviral activity. And so, we decided to test for antibiotic activity.”
By activity, Andersh is referring to the ability of these compounds to either kill or inhibit the growth of bacteria. “We found that they had weak antibiotic activity, so we decided to play around with the structure a bit.” It’s well known, he says, that small structural changes can have vast implications on a compound’s biological activity. “And through that work, we’ve been able to improve the ability of these compounds to inhibit the growth of bacteria by almost 1300 percent. We’re now approaching the levels you would commonly see in commercial antibiotics.”
The compounds being examined by Andersh and his team are known as racemic mixtures, combinations of two variations of the same chemical, indistinguishable under normal conditions. “They have the same chemical formula, and the physical properties are exactly the same,” says Andersh. “Everything is identical, except one is the mirror image of the other.”
Some of our most common drugs are racemic mixtures, including ibuprofen and omeprazole, better known by its trade name, Prilosec. When they are ingested, one form of the drug will interact with specific proteins or enzymes to bring about the desired analgesic effect, while the other is flushed out of the system.
“Think about it in terms of putting your hand in a glove,” Andersh explains. “Say the glove is an enzyme cavity. The right hand fits into that cavity correctly, but the left hand doesn’t. More than likely, only one of these two forms of the drug has the biological activity. And so, we need to identify which form—called an enantiomer—has the activity.”
The challenge for drug makers today, however, is that in order for a new drug to be approved by the FDA, it must be demonstrated that neither of these enantiomers has significant side effects in humans. “Now, you have to do independent testing of each of those two ‘hands.’ You’ve just doubled the expense of getting FDA approval, which is already very expensive.”
The Evolutionary Conundrum
“It’s basically survival of the fittest,” says Andersh, describing the process by which bacteria gain antibiotic resistance. “A colony of bacteria will have a genetic mutation; they survive and replicate. You’ve now created a modified strain that’s a little more resistant to the drug. As the patient continues to take antibiotics, a few more bacteria have genetic mutations and are able to survive. They replicate, and you’ve now created bacteria that are even more resistant.” This continues ad infinitum, with dire implications in some cases.
It’s estimated that nearly two million people in the United States will acquire a bacterial infection in a hospital this year, resulting in 90,000 deaths and $20 billion in excess healthcare costs, according to the Centers for Disease Control and Prevention. Nearly three quarters of the bacteria causing these infections are resistant to one or more of the antibiotics used to treat them. It seems we are indeed in a crisis of antibiotic resistance, the reasons for which are myriad.
The World Health Organization estimates that more than half of all medications are prescribed inappropriately or incorrectly—and half of all patients fail to take them correctly. The use of broad-spectrum antibiotics, which kill many different types of bacteria, as opposed to narrow-spectrum ones, which target specific bacteria but require additional diagnostic testing, is another factor. So is the overuse of antibacterial agents in common household products. In addition, there is growing evidence to suggest that the use of antibiotics in livestock—not to fight infection, but to promote growth in healthy animals—may be accelerating the problem. In essence, bacteria are continually finding ways to outsmart us, and we are assisting them in their evolutionary quest for survival.
In a sense, we’ve become the victim of our earlier successes, as the effectiveness of previous generations of antibiotics led pharmaceutical companies to turn their attention to other areas. Today, bacteria are evolving much faster than new antibiotics can be brought to market. It’s become a cat-and-mouse game, as drug makers try to keep up with an ever-changing adversary. But given that it takes a decade and a half (and about a billion dollars) to bring a new drug to market—not to mention all of the regulatory hurdles—it’s a race that’s more difficult than ever before.
And then there is the issue of financial incentives—or rather, the lack thereof. A drug to treat diabetes, for example, offers the likelihood of a vast pool of potential customers, and because it’s a lifelong disease, they would likely remain as such for a long period of time. On the other hand, treatment for a bacterial infection may last just five to ten days. There is simply not as much profit in it for the drug companies, who, after all, must make money to stay in business.
But Andersh is careful not to assign blame for the predicament. “Some people want to blame the medical community,” he says. “Some want to blame the agricultural industry. Some want to blame the patients. Some want to blame the pharmaceutical companies. But it’s a shared blame.
“It is what it is,” he continues. “It’s a challenge we face as a scientific community, and we need to work on this problem and try to come up with solutions.” To that end, Drs. Andersh and Johnson and their team continue to work on structural refinements to these compounds to make them more effective at inhibiting bacterial growth, while seeking to identify which of the two “hands” is the active one. But it’s a slow process.
“You run into a lot of dead ends,” says Andersh. “You might think, ‘Aha, I’m finally understanding what’s necessary structurally to improve the antibiotic activity’—and then you make the next modification and find out you were wrong. Then, you’ve got to go back, examine your results and look for the next lead. It’s kind of like a maze: you come to a wall, back up and hope you get further next time. Eventually, you hope you can get to the other side.”
On the Front Lines of Battle
Despite their initial success, Andersh is skeptical that their research will lead directly to a new, FDA-approved drug anytime soon. “The chances of an academic scientist developing a commercial product are very, very slim,” he says. “We’d have to start testing against human pathogens, and we don’t have a license to work with those types of materials—nor would I want one. Then, the next step is animal testing—you’re not going to go right from the petri dish to testing in humans. Finally, FDA approval is so expensive that an institution like Bradley would have a hard time affording that on its own. However, if we cross a certain threshold, we may seek to find a commercial partner.”
But there are other motivations driving Andersh. “Why I do what I do is to provide opportunities for our students to gain exposure to research so they can decide if they enjoy it and want to pursue a career in that field. Secondary to that, but a nice benefit, is that we’re adding to the body of knowledge, with the hope that one of our discoveries will lead to another discovery that may lead to another discovery…that may ultimately lead to a solution to a societal problem.”
The problem could hardly be more serious, and the scientific and medical communities are waking up to its enormity. Last September, the Pharmaceutical Research and Manufacturers of America, which represents the nation’s leading pharmaceutical companies, convened leaders from government, industry, academia, medicine and science at a major conference to discuss the lack of new antibiotics for fighting drug-resistant bacteria, as well as potential solutions for the many challenges of getting new drugs to market.
“Unless we address this crisis now,” said Dr. David Gilbert, who chairs the Antimicrobial Availability Task Force of the Infectious Diseases Society of America, “we face a future more like the days before antibiotics were developed, a time when people died of common infections, and many of the medical advances we take for granted today—including surgery, chemotherapy and organ transplants—are no longer possible.”
If that sounds alarmist, better that than the hubris mistakenly displayed by the Surgeon General some four decades ago. The war against infectious disease has hardly been won, and researchers like Drs. Andersh and Johnson are right there on the front lines of battle. iBi
Update: On April 11, 2012, the FDA announced a new rule that would prohibit farmers and ranchers from feeding antibiotics to cattle, pigs and other animals without a veterinarian's prescription.