It was a “connect-the-dots” moment for Cameron Currie, PhD.
While working on his doctorate degree in bacteriology at the University of Toronto in the 1990s, Currie was studying ants that grow fungus as their food source. He was the first to discover that leaf-cutter ants also employ a bacterium to protect the fungus against parasites.
That study conclusion got Currie’s wheels turning. Believing that this might be more common in nature, he discovered that a bacterium used by southern pine beetles to protect their fungus farms contains an antibiotic never before seen in science.
“I thought, ‘Wouldn’t it be exciting if many insects have discovered, through evolution, the benefits of obtaining antibiotics from bacteria?’” Currie recalls. “When my research partner, Harvard chemist Jon Clardy, and I looked into it, we had an ‘ah-ha’ moment. Our theory was correct.”
Photographed through the acrylic chamber that contains a leaf-cutter ant colony, David Andes (PG ’96) (left) and Cameron Currie witness the herculean tasks and teamwork required for the ants to harvest bits of leaves. The leaves nourish the colony’s fungus gardens, which serve as the ants’ primary food source.
Now a professor of bacteriology in the University of Wisconsin College of Agricultural and Life Sciences (CALS), Currie notes that his work led to a highly collaborative research project - among CALS, the UW School of Medicine and Public Health (SMPH) and the UW School of Pharmacy.
Currie and David Andes, MD, PhD (PG ’96), professor and chief of the Division of Infectious Disease in the Department of Medicine, are co-principal investigators of a multidisciplinary study designed to find untapped sources of new antibiotics. Their goal is to help address one of the most compelling problems of the 21st century: antibiotic-resistant bacterial infections.
'An Imminent Global Public Health Threat'
The Centers for Disease Control reports that more than two million people per year in the United States suffer from antibioticresistant infections. Seventy percent of people who die from hospital-acquired infections are those who do not respond to antibiotics. Because these drugs have been used so widely, the diseases they are designed to kill have adapted to them.
“Drug resistance and lack of new antibiotics represent an imminent global public health threat,” explains Andes, who did his internal medicine residency and infectious disease fellowship at UW Hospital and Clinics, where he cares for patients in the infectious disease and travel medicine areas. “There are patients in almost every hospital with infections that have absolutely no treatment available.”
With this in mind, the Andes/Currie research team is focusing on developing new treatment options for bacteria that are responsible for the majority of U.S. hospital-acquired infections and for fungi-associated infections in immunocompromised patients, such as those with cancer and those who have undergone organ transplants.
Traditionally, the pharmaceutical industry focused on soil as the origin of new antibiotics. But because this once-rich source of drugs has been mined heavily for many years, it now turns up only the same microbes. As the rate of hospital-acquired infections increased, the pharmaceutical industry found it financially unfeasible to search for new antibiotics.
“In the 1980s, pharmaceutical companies were submitting approval requests to the Food and Drug Administration (FDA) for 10 to 20 antibiotics each year,” notes Andes. “Over the past 20 years, the number of antibiotics developed has decreased 80 percent. Between 2008 and 2012, only three antibiotics were submitted to the FDA for approval, but none were novel.”
Leaf-cutter ants grow fungus as food and employ a bacterium to protect the fungus from parasites.
The National Institutes of Health (NIH) awarded the Andes/Currie team a five-year, $16 million Centers of Excellence grant to develop a robust and sustainable antimicrobial discovery pipeline. Expanding upon Currie’s earlier research, the scientists are examining other natural sources, including animals, insects and marine life that harbor bacteria.
“The pool of insect species alone is massive,” says Currie, noting that an estimated 10 million species of insects live on the planet.
Reflecting on the urgency of their work, Andes states, “We’ve found a completely new paradigm for finding new anti-infectives. But in addition to finding microbes that could be sources of new drugs, we have novel ways to find the antibiotics themselves and test them rapidly. We don’t waste time.”
He describes their research thrust as a “mini pharmaceutical company” - the UW Antimicrobial Drug Discovery and Development Center - that started to take shape in 2007 with funding from the School of Medicine and Public Health's Wisconsin Partnership Program (WPP) and NIH Challenge grants.
“Our team’s seminal advances relate to identification of rich, diverse, untapped sources of novel natural-product microbials,” shares Andes. “These drug sources are selected from symbiotic environments, in which two things evolve together, between an animal and a microbe. The microbe provides colonizing bacteria that produce molecules to defend the animal from infection.”
Approaching the Problem from Many Perspectives
Andes says this fresh approach evolved because people from different but complementary fields have gotten together to think about the challenge from different perspectives. In addition to infectious disease and bacteriology experts, the research team includes scientists in pharmaceutical services, medical genetics, pediatrics, oncology, public health, medical microbiology and immunology, biological chemistry and molecular pharmacology.
Their process begins with the collection of insects and marine life from places near and far. Currie has searched in Madison and Florida and hopes to do the same in Hawaii and Alaska.
“I look under logs and rocks and inside logs, and I analyze insects that fly, beetles that burrow in woody materials and ants that live in colonies,” describes Currie, whose huge, active leaf-cutter ant colony in the UW Microbial Sciences Building draws inquisitive visitors from throughout the community.
While Currie collects samples from insects that live almost entirely on land, his colleague Tim Bugni, PhD, captures marine life in places like the Florida Keys and Puerto Rico. An assistant professor in the UW School of Pharmacy, Bugni has collected marine invertebrates - such as sponges and sea squirts - that have complex symbiotic bacterial communities.
After they collect samples, Currie and Bugni grow and screen microbes in petri dishes. Their first hurdle, which may take three months, is to systematically identify strains that have the most promise for antibiotics. Currie follows with genomic testing to determine which strains have the most potential for promising drug leads. The scientists then chemically analyze the strains’ structures.
Sometimes the compounds do not duplicate in the laboratory, even though genomic testing shows that they should. In such cases, scientists try to coax organisms to make compounds by mimicking the organism’s environment.
“Coming up with a consistent way to do that is challenging,” says Bugni. “It took two years to come up with the process of reproducing stubborn organisms that would not cooperate in the lab environment.”
The next step is a math problem, Bugni explains.
“For example, we’ll take a piece of a sponge, 50 percent of which is bacteria, and cultivate the bacteria,” he says. “Using metabolomics, a statistical way to search for unique chemical fingerprints, we are able to home in on newly found microbes.”
The scientists take a subset of strains and use high-throughput testing before handing them off to Andes, who evaluates them in mouse models. Once that is successful, they turn to the pharmaceutical industry to conduct clinical trials.
“Our process is on the order of magnitudes more efficient than traditional pharmaceutical indstry methods. We can do everything up to human clinical trials,” notes Andes. “We’re finding large numbers of new compounds at a rate 100 times greater than what the pharmaceutical companies ever did.”
Currie adds, “Antibiotic development can take up to 15 years from sample collection to clinical trials. We have a goal to make this much faster.”
Blazing a New Trail
The team’s successes back up these claims. Currie has uncovered more than 20 drug leads and Bugni has found more than a dozen. Andes says the team already has promising compounds to combat methicillinresistant staphylococcus aureus, fungi and pseudomonas infections.
Andes states his admittedly lofty goal: to find one promising new drug lead in each of the five years of the NIH grant.
Reflecting on history, he notes that the discovery of antibiotics was among the most important medical advances of the 20th century.
“The use of penicillin in World War II made it the first war in which more people died from weaponry than from bacterial infections,” Andes says. “A little-known fact is the key role that UW-Madison played in discovering mold strains and fermentation methods to scale the production of penicillin, which made the drug available for mere pennies during the war effort.”
He concludes, “The 21st century beckons another trail-blazing effort in antimicrobial development on our campus.”
This story was originally published by the University of Wisconsin-Madison School of Medicine and Public Health on Sept. 4, 2014.