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Can science ward off a global drug crisis?

If you were to develop one of the highly drug-resistant strains of tuberculosis, your survival might come down to a dose of capreomycin. For doctors trying to fight these newly emerging strains—the most dangerous form of the common bacterial infection—this antibiotic is a drug of last resort. If it doesn’t work, the fight is essentially done. “It doesn’t matter what you give them after that,” says CALS bacteriologist Michael Thomas. “You can’t treat them.”

Many forms of microbial life have the ability to produce antibiotics, from red-hued fungi growing in a Petri dish to bacteria that live in the frozen soils of Alaska.

While much of the planet is already facing a TB epidemic—2 million people died from the disease last year and as many as 2 billion are carriers—things could be much worse without capreomycin. It is deemed so valuable that it is listed as one of the planet’s essential medicines by the World Health Organization. Because bacteria evolve resistance to the weapons we throw at them, doctors are being urged to use capreomycin sparingly to preserve its killing power until something better comes along.

But new antibiotics rarely come along. During the past 38 years, only two truly novel antibiotics have been discovered, and pharmaceutical companies have largely backed away from the business of tweaking existing antibiotics to enhance their power. Capreomycin, for instance, was discovered in 1956.

The lack of activity on antibiotics is partly due to the early success of those drugs. They worked so well—and everyone assumed they’d continue working ad infinitum—that many large pharmaceutical companies dropped their antibiotics discovery programs. By the time drug resistance became a recognized problem, it no longer made sense to restart them. “It costs an obscene amount of money to develop a drug now,” explains Thomas. “And there just isn’t enough money (to be made in antibiotics) because when you take an antibiotic you get cured.” Drug companies prefer the profit potential of medicines for chronic conditions such as high cholesterol, where patients may spend years or decades on a medication.

Pharma’s disinterest has created a potentially explosive situation where our bacterial foes have evolved while the drugs to fight them mostly haven’t. In microbiology circles, people are saying there will be 15 untreatable infections within the next 25 years if things don’t change quickly. “Sometimes I feel like I’m being a doom-and-gloom, Chicken Little type,” says Jo Handelsman PhD’84, chair of the bacteriology department. But the talk she’s hearing lately tells her “it’s even scarier than I say it is.”

Bacteria that live in the frozen soils of Alaska, here studied by CALS researcher Lynn Williamson.

But the urgency has brought on a paradigm shift within the research community. Scientists who for decades devoted themselves to basic research have shifted gears to discover new antibiotics and improve existing ones. And they’re getting support from agencies such as the federal National Institutes of Health, which has embraced the notion that academics can help bring the next generation of antimicrobials to market.

“A few years ago if I had said, ‘I want to make new drugs in my academic lab,’ the NIH would have responded, ‘That’s not the kind of work we fund,’” says Thomas. “Now they are taking it very seriously, supporting the type of research that discovers new anti-infectives, because they know there’s this gap now.”

The next generation

Before antibiotics, contracting a microbial infection was often a matter of life and death. Created by bacteria and fungi to kill off competing microbes, these molecules were first co-opted by Western medicine during World War II, when penicillin worked wonders warding off infections in military hospitals. That success launched a flurry of drug discovery, during which antibiotics were located and refined as treatments for many conditions, including cholera, typhoid fever, malaria and staph infections. But over time, the bugs adjusted, and many diseases that we once considered defeated have re-emerged. And new ones have cropped up, including so-called “superbug” infections that resist virtually all known antibiotics.

In the lab, Michael Thomas is using NIH funding to try to extend the life of capreomycin, as well as its close cousin, viomycin. Capreomycin was originally discovered in a bacterium called Saccharothrix mutabilis, which does not lend itself to genetic manipulation and thus limits the ability of researchers to re-engineer its production. But Thomas transferred the entire gene cluster from the original bacterium into another host that was easier to work with. He now knows the sequence and function of all of the genes involved in the production of the two antibiotics, allowing him to mix and match genes and change the nature of the antibiotics that the bacteria produce. Through this work, Thomas’s team has created 10 new compounds based on the structures of capreomycin and viomycin. And while these were made to prove the process works, each has a chance of becoming a real drug. Thomas’s lab will complete the initial testing of antibiotic activity and then forward promising candidates to the feds.

“The nice thing about having NIH funding is that if we have something above a certain minimum (antibiotic activity level), the NIH will actually take the molecule—if you can provide them with enough of it—and do the mouse models and the in vitro analysis to figure out if it is actually a promising drug,” he says.

In the case of TB, the need for such new drugs is acute. Worldwide, 2 billion people carry the bacteria that cause TB—one of every three people on the planet. And while most of those people have the ability to keep the disease at bay, approximately 8 million people suffer from the active form of the disease, which causes lung damage that in severe cases can be fatal. In the United States, TB causes more deaths than AIDS, and as many as 10 million people are believed to carry the latent form.

In Marcin Filutowicz’s lab, student Carly Campbell probes bacteria in search of molecules that block plasmids, the small pieces of DNA that microbes swap to gain resistance to antibiotics designed to kill them.

About 40 years ago, when more than a handful of powerful anti-TB drugs were still working, public health officials declared this disease eradicated, at least in the developed world. But “TB never really went away,” explains Thomas. “It’s a disease of civilization, and it spreads very easily. So wherever you have a lot of people living in a confined environment, you’re going to have TB.” This makes drug development critical for warding off the spread of the deadlier, drug-resistant strains of TB. Because the global threat is so great, several companies have agreed to take whatever promising molecules that researchers like Thomas produce in the lab and build them further.

To Handelsman, this model represents an intriguing way to get more new antibiotics into the pipeline. It’s clear why pharmaceutical companies are reluctant to jump back into antibiotic discovery. The costs of research, development and clinical trials, combined with the limited window offered by patent protection, makes investing in the area risky. Handelsman says pharmaceutical company representatives have reminded her that they’re not in business to do things out of the goodness of their hearts; they have an obligation to shareholders to pursue profitable strategies. “And that’s a reasonable position,” she says. “If they can’t make the books balance, it would be irresponsible for them to do it. On the other hand, someone has got to take responsibility for solving this crisis.”

The solution will likely require some direction from the federal government, which could either change the patent rules to make antibiotics research more alluring or fund nonprofit groups to take over. But the partnership approach being taken with TB drugs may be even more appealing, Handelsman says. “If academic labs did the hard part—the discovery part—and took antibiotics to a reasonable level of discovery, like animal trials or something like that, I think the drug companies would pick them up,” she says.

The natural solution

By genetically tweaking the structure of the antibiotic capreomycin, bacteriology professor Michael Thomas has engineered 10 new compounds that may turn out to be more effective in treating highly drug-resistant forms of tuberculosis.

But engineering antibiotics is not the only approach. Handelsman is among a group of CALS scientists who believe that we’ve far from discovered the best that nature has to offer in fighting microbes. In her case, she’s studying soil, which has been a rich source of antibiotics in the past. Approximately two-thirds of the antimicrobials used in medicine today trace their origins to soil microbes, which use these small molecules—much as we humans do—to engage in microbial warfare. In the soil, bacteria and fungi release antibiotics into the environment to kill or inhibit the growth of their neighbors and give themselves a competitive advantage in the hunt for resources and territory. But Handelsman, who studies how microbial communities function, suspects these small molecules may also play a second, more subtle role in microbial community dynamics.

“Many antibiotics are produced at levels that are too low to be inhibitory,” she says. “So we’re exploring the hypothesis that antibiotics are actually signaling molecules, and that at low concentrations they provide bacteria with a way of (communicating with) each other.”

In the past, Handelsman’s efforts to understand the inner workings of microbial communities were hampered by the very nature of these organisms. Only a tiny fraction of soil microbes—as few as 1 percent—can be grown in test tubes and on Petri dishes, meaning that scientists hadn’t really even made a dent in observing microbial communities. Handelsman helped develop a revolutionary method known as metagenomics that unlocks this world. Using metagenomics, scientists can access all of the genetic material in a microbial sample without having to grow a thing, which is expected to open up a host of previously inaccessible antibiotics. “Because the culturable organisms in the soil produce antibiotics, we’re predicting that the unculturable ones do as well, and maybe they produce different ones,” says Handelsman.

Metagenomics has already helped unearth a novel antibiotic in another kind of natural system. CALS bacteriologist Cameron Currie used the technique on a colony of leaf-cutting ants to get a genetic picture of the bacteria that help the ants protect their food source from fungal invaders. The ants harbor these beneficial bacteria in small cavities in their bodies and use the antibiotics they produce to kill off the fungi that attack their larders.

Another CALS bacteriologist is taking a different tack by manipulating microbial DNA to find new antibiotics. Nancy Keller found a way to trick a kind of fungus that she studies into ramping up production of all the antibiotics and other accessory chemicals it is capable of making. The approach has shown that fungi, even well-studied ones, have the capacity to produce significantly more antibiotics than scientists originally thought. Keller says the approach is likely to work on other closely related fungi, meaning it could be used to search across hundreds of fungal species for promising new drug candidates.

Plasmid assassin

While his colleagues search soils and other natural systems for new antibiotics, Marcin Filutowicz makes a compelling point: Why do we even need to rely on antibiotics to kill microbes? Other approaches might work just as well, if not better.

Filutowicz, also a professor of bacteriology, favors plasmids, which are small, auxiliary pieces of DNA that microbes often carry in addition to their core chromosomal DNA. Normally, plasmids are a boon—containing genes for antibiotic resistance, for instance—and microbes readily swap them around. Filutowicz, however, figured out how to turn these genetic elements against their hosts.

To make it work, Filutowicz created a renegade bacterium capable of swapping designed-to-kill plasmids with targeted pathogenic microbes. Once inside, the plasmids replicate uncontrollably until they kill the organism. “This technology is based on the idea that we can use the good bacteria in our bodies to combat the bad guys,” says Filutowicz. “It’s a versatile concept that doesn’t apply to just one infectious agent.” In 2002, Filutowicz cofounded a company called ConjuGon to begin developing killer plasmids for the commercial market. The company has produced a plasmid treatment to ward off a drug-resistant infection in burn wounds, which is administered by rubbing the plasmid-delivering bacteria directly on the affected tissue. Already, this approach has proven successful in animal trials. “It’s a terrible pathogen nowadays,” says Filutowicz of the bacterium that causes the infection. “Soldiers are dying because of this. It’s resistant to all clinically relevant antibiotics, so the (U.S.) Army is very much interested in this technology.” Not surprisingly, the U.S. Department of Defense has been a big supporter of ConjuGon’s work over the past few years.

Fungal spores light up the monitor of a digital microscope as research associate Taylor Dagenais examines how they interact with white blood cells. Fungi produce an array of chemicals that can be toxic to both humans and pathogenic microbes, an ability that researchers believe may point them toward novel antibiotics.

These days, Filutowicz is at work developing a second plasmid-centric antimicrobial technology. In this case, the plan is to deploy small molecules to strip away the plasmids that allow microbes to produce toxins, resist antibiotics and pass these traits on to others. The key thing about this technology is that, by getting rid of antibiotic resistance genes, it has the power to rejuvenate older antibiotics, giving powerless drugs the ability to kill again.

“This is like a new venture into a new class of antimicrobials that do not kill, but they attenuate bacteria. They disarm bacteria,” says Filutowicz, who recently received NIH funding to develop this technology against Salmonella enterica, the type of bacterium that causes salmonella poisoning. For this project, Filutowicz will collaborate with Handelsman and Thomas, a strategic partnership that gives him access to Handelsman’s metagenomic libraries to search for plasmid-displacing molecules specific for salmonella, as well as access to Thomas’s molecule-tweaking skills.

More than anything, Filutowicz would like to see a drug from one of his antimicrobial technologies come to market. Preferably more than one. He feels microbiologist have a moral obligation to do application-oriented work, and in order to promote this kind of work among his colleagues, he and Handelsman founded the Wisconsin Project for Antimicrobial Research, an initiative designed to bring campus scientists together in synergistic ways to develop new antimicrobial technologies.

“Madison’s community of microbiologists is one of the most prominent and diverse in the nation, and our obligation to society is not only to produce basic knowledge, but to produce knowledge that can benefit people relatively quickly,” he says. “I’d like to see the practical applications of the things we are working on become available within five to ten years.”

So what to do while we wait for new treatments to become available? Simple: Wash your hands. “This is the oldest kind of public health problem, and the solution must encompass everything from the simplest things—from (people) simply washing their hands well—to the really high-tech solutions once people get these diseases,” says Handelsman. “Personally, I think we should get rid of hand shaking as a cultural custom because it’s really not very healthy.” These are the kinds of small sacrifices we may soon need to make, measures that can help keep us safe until we find new weapons and regain the upper hand in this unending battle against our microbial foes.

SIDEBAR — How a Superbug is Born

In nature, microbes can become resistant to antibiotics in a couple different ways. One is through random mutation. This occurs when chance errors occur in an organism’s genetic code, giving it resistance to a given antibiotic. But microbes can pick up resistance genes by swapping small pieces of DNA – known as plasmids – with neighboring bugs. Once resistance is acquired, it gets passed on to all of the microbe’s descendants. Typically, resistance genes allow microbes to fight back against antibiotics using one of these three methods:

Illustration by Robin Davies

Pump and Run (blue)

In this model, microbes pump the antibiotic out of the cell, where the drug can’t do them any harm.

Interior Remodeling (yellow)

A few microbes have the ability to alter the structure of cells or molecules under attack by an antibiotic, minimizing damage and allowing the microbe to survive.

Cut the Cord (green)

Some microbes deploy special proteins that cut antibiotic molecules into pieces, rendering them powerless.