A New Weapon Against Bacterial Disease

Bacteria that are resistant to antibiotics are one of the biggest problems facing public health today. About 800,000 children worldwide die before their fifth birthday from diarrheal diseases that evade treatment. The concentration of those diseases is highest in parts of Africa and Asia.

To address the problem, CALS biochemist Srivatsan (“Vatsan”) Raman hopes to harness the power of phages—viruses that infect bacteria but leave humans unscathed. With help from a grant from the Bill and Melinda Gates Foundation, Raman’s team is designing phages to specifically target bacteria that are causing diseases in infants.

Raman describes antibiotics—how doctors usually fight infections—as hammers that take out many bacteria, both harmful and beneficial. This means they can affect the entire human microbiome, which is the community of microbes on, inside and around the human body.

“We do not yet have the tools to selectively edit the composition of a microbiome,” Raman explains. But that is one of the goals of his lab’s work with phages. Unlike antibiotics, phages are very specific. A phage only infects one type of bacterial host. It is this specificity that presents Raman and his researchers with opportunities—but also some challenges.

Phages, which resemble lunar landers, locate bacterial hosts by attaching to specific receptors on the cell’s surface. Once they have found their host, some phages, called obligate lytic phages, quickly infect the cell and replicate. Once replication is complete, the new phage progeny burst out of the cell, ready to infect and kill the next available host.

Raman’s goal is to be able to control many steps in this process. He is investigating a way to engineer a phage that can be programmed to target specific bacteria. By changing just the “legs” of the lunar lander, the designer phage can target and eliminate any bacteria the researchers wish.

However, while destruction of bacteria is the ultimate goal, the process also creates problems. Many bacteria contain toxins that are released if the bacteria die in large numbers. So Raman’s team is also trying to control the rate at which phages infect and kill cells inside the body. “We can keep the phage on a leash and determine when and where it can infect,” describes Kelly Schwartz, a postdoctoral fellow in Raman’s laboratory.

Raman believes “designer phages” have great promise for human health.

“I was drawn to this research because designer phages can provide a potential solution to the antibiotic resistance problem,” notes Raman. “These bacteria are resistant to anything you throw at them and are killers in developing countries.

“And the next question, if we are successful, is ‘How can we turn these phages into actual medications that can be delivered to these areas?’ That challenge awaits us further down the road,” Raman says.

Vatsan Raman in his lab: The biochemist is engineering viruses that can vanquish harmful bacteria. Photo by Robin Davies/UW–Madison MediaLab at Biochemistry

The Drugs Start Here

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.”

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.

Our bacterial foes have evolved while the drugs to fight them mostly haven’t.

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.”

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.”

George Golumbeski

Earlier this year, Golumbeski left his job at pharmaceutical giant Novartis, where he had been vice president of business development, to take the reins of the Austrian biotech company Nabrivia Therapeutics. As chief executive officer, he oversees a 55-person team working on the next generation of antibiotics—including three developmental products designed to fight methicillin-resistant staphylococcus aureus, a frightening bacterial infection that doesn’t respond to common antibiotics. Golumbeski enjoys tackling the scientific, organizational and fiscal issues in bringing new drugs to patients. “After nearly 20 years,” he says, “my work remains fresh, complex and very challenging.”