'Predatory Bacteria' Might Be Enlisted In Defense Against Antibiotic Resistance

Sep 6, 2018
Originally published on September 6, 2018 3:27 pm

Here's a bold idea to fight back against bacteria that can't be stopped by antibiotics: Go after them with germ-eating microbes. That reasoning lies behind an intriguing line of research that might also be put to use in the event of a germ-warfare attack.

It might seem strange to think of microbe-eating microbes, but "actually they're found in almost every ecosystem on Earth," says Brad Ringeisen, deputy director of the Biological Technologies Office at the Defense Advanced Research Projects Agency.

They're even living inside us, but at levels so low that they aren't effectively battling back against dangerous germs. DARPA has been funding research to see if these predatory bacteria can be harnessed as our allies.

"It's been very exciting," Ringeisen says, as this exploratory phase of research is gradually coming to a successful conclusion.

Lab studies that his agency has funded show that the predatory bacteria will attack all sorts of nasties, including bacterial lung infections, the plague and deadly germs that have developed resistance to antibiotics. And the star of this show is an organism called Bdellovibrio, a bacterium that swims around with the aid of a corkscrew tail, and attacks common germs six times its size.

"Bdellovibrio ended up preying upon 145 of the 168 human pathogens we tested, which is pretty remarkable," Ringeisen says. Other species of predatory bacteria are also potentially useful, and each uses its own strategy.

Myxococcus "can use what's referred to as a wolf pack" strategy, where they swarm their prey, Ringeisen says. "There are also organisms that act almost like a vampire" — the Vampirococcus — which suck the life out of their prey.

The best-studied predator, Bdellovibrio, actually bores into larger bacteria and eats them from the inside out.

First, it uses its flagellum, which is stiff and rotates, to swim up to prey. Then it latches on, using tiny appendages "which are little grappling hooks on the surface," says Liz Sockett, a professor of bacterial genetics at Nottingham University in the UK. It's a bit like a climber attaching to rock, she says.

Once the Bdellovibrio has grappled its prey, it latches on tight with multiple mechanisms.

"I joke with my students sometimes that they're attaching with a grappling hook, a rope, some duct tape and some Blu Tack [adhesive putty]," she says.

This is not just a weird and wonderful process. The rather blunt-force attack means the germs don't appear to be able to develop resistance to assault — any more than zebras can develop resistance to lions.

Colleagues in Sockett's lab have looked hard for evidence to the contrary.

"They took the bacteria that had been preyed upon by Bdellovibrio every week and looked for any small survivors in the culture," Sockett explains. They fished out the few survivors, let them multiply, and then let the Bdellovibrio attack them again. If resistance were to develop, this is exactly the scenario where it would appear. Her colleagues "did this 50 times over a long period," she says, "and we never got any direct mutants that were resistant."

So Bdellovibrio can effectively kill nearly 150 disease-causing germs and the preyed-upon can't evade it. Sounds like it could be incredibly useful.

Nancy Connell, a microbial geneticist who worked for years at Rutgers University studying anthrax and all sorts of other deadly and ominous germs, says exploring these predatory bacteria is the most exciting work she's done in her career.

"This is the first time that I have felt we might have a way through many of these different infections," says Connell, who has since moved to the Johns Hopkins Center for Health Security in Baltimore.

After seeing all the promising work in test-tube studies, Connell and her lab got DARPA funding to see if the germs would actually fight lung infections in rats. The answer was yes. "So that was actually our first and very exciting result," she says.

The predators didn't entirely wipe out the disease-causing bacteria, as antibiotics might. That makes sense, because predators rarely eradicate their prey. Connell's colleague at Rutgers, Daniel Kadouri, notes that when lions eat too many zebras, they have trouble finding the few remaining, and that allows the zebra population to survive.

But unnaturally large doses of Bdellovibrio can reduce bacterial populations by a lot. "We're talking about 99.99 percent, depending on the [animal] model we're using," Kadouri says.

And even though it might sound creepy to consider deliberately infecting people with bacteria, extensive safety studies suggest that would be OK.

Still, when it comes to experimenting on humans, Kadouri is planning to start out with small steps – perhaps treating a local infection from a burn or wound, or a lung infection.

Could predatory bacteria ever become a replacement for antibiotics? Sockett doesn't think so. She suspects that if doctors gave a big dose of this bacteria to people, the patients would develop an immune response to it that would hobble future treatment attempts.

"You get one shot at using the Bdellovibrio," she says. "We would call this a fire-extinguisher approach, which is where you use the fire extinguisher to put out the fire. But if the fire extinguisher doesn't work, you can't go back for a second fire extinguisher."

Still, the approach could be useful if given as a one-off preventive in advance of an anticipated germ warfare attack, or it could also work in a patient who has an infection that simply doesn't respond to antibiotics, Connell says.

Of course, we won't know whether it works at all in people until researchers can put it to the test. That's the next step, and a big one.

You can reach Richard Harris at rharris@npr.org.

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STEVE INSKEEP, HOST:

People say you fight fire with fire. Well, maybe you can also fight tiny microorganisms with other microorganisms. For bacteria that cannot be stopped by antibiotics, you may be able to go after them with germ-eating predators. Scientists hope they may even be able to use these predators in the event of a germ warfare attack. Here's NPR Science correspondent Richard Harris.

RICHARD HARRIS, BYLINE: Nature is filled with predators, so it's no surprise that there are predators that hunt down and kill bacteria. And it turns out that some of these predators or other types of bacteria.

BRAD RINGEISEN: Actually, they're found in almost every ecosystem on Earth.

HARRIS: Including inside of us. Brad Ringeisen became fascinated with these critters after he took over a program at the Pentagon's Defense Advanced Research Projects Agency. DARPA's aim - to figure out if they could be harnessed to protect us from disease-causing bacteria.

RINGEISEN: It's been very exciting.

HARRIS: Lab studies that his agency has funded showed that the predatory bacteria will attack all sorts of nasties, including tuberculosis, the plague and deadly germs that have developed resistance to antibiotics. And the star of this show is an organism called Bdellovibrio, an extra-small bacterium that swims around with the aid of a tail.

RINGEISEN: Bdellovibrio ended up preying upon 145 out of the 168 human pathogens that we tested, which is pretty remarkable.

HARRIS: And different species of predatory bacteria use different strategies to attack.

RINGEISEN: They can use what's referred to as a wolfpack.

HARRIS: In which they hunt in a group.

RINGEISEN: There's also organisms that act almost like a vampire.

HARRIS: They suck out the innards of their prey. Bdellovibrio actually bores into larger bacteria and eats them from the inside out. Liz Sockett, who studies them at Nottingham University in the U.K., says they swim up to their prey and latch on using tiny appendages...

LIZ SOCKETT: Which are little grappling hooks on the surface of the Bdellovibrio that make initial attachments, a bit like a climber attaching to rocks.

HARRIS: This is not only weird and wonderful but this rather blunt-force attack means that bacteria don't seem to be able to develop resistance any more than zebras can develop resistance to lions. Her colleagues have looked hard for evidence to the contrary.

SOCKETT: They took the bacteria that had been preyed upon by Bdellovibrio every week and looked for any small survivors in the culture, grew them up again and offered the same bacteria back to the Bdellovibrio. And they did this 50 times over a long period. And we never got any direct mutants that were resistant.

HARRIS: So here's an organism that can effectively kill nearly 150 disease-causing germs, and the preyed-upon can't evade. Sounds like they could be incredibly useful. Nancy Connell, who worked for years at Rutgers University studying anthrax and all sorts of other ominous germs, says exploring these predatory bacteria is the most exciting work she's done in her career.

NANCY CONNELL: This is the first time that I have felt that we might have a way through many of these different infections.

HARRIS: After seeing all the promising work in test-tube studies, Connell and her lab got DARPA funding to see if the germs would actually fight infections in rats. The answer was yes.

CONNELL: And so we were able to reduce the number of bacteria in a lung infection in an animal model by treating with the predator bacteria. So that was actually our first and very exciting result.

HARRIS: The predators didn't wipe them out entirely as antibiotics might. That make sense because predators rarely eradicate their prey. But her colleague at Rutgers Daniel Kadouri is optimistic that the predators are doing enough.

DANIEL KADOURI: We can reduce the numbers to quite a lot. We're talking about 99.99 percent depending on the model that we're using.

HARRIS: And Kadouri says, even though it might sound creepy to be deliberately infecting people with bacteria, this seems to be quite safe. They're thinking now about relatively simple experiments in people.

KADOURI: We imagine something which is localized, such as a burn infection, a wound infection or a lung infection, will be much more efficient than doing, for example, like a blood infection that it's going to be more difficult for the predator to find the prey.

HARRIS: Could this end up being a replacement for antibiotics? Liz Sockett in Nottingham doesn't think so. She suspects that once you give a big dose of this bacteria to people, they will develop an immune response to it that would hobble future treatment attempts.

SOCKETT: You would get one shot at using Bdellovibrio. So in England we would call this a fire extinguisher kind of approach, where you use the fire extinguisher to put out the fire. But if the fire extinguisher doesn't work on the fire, you can't go back for a second fire extinguisher.

HARRIS: Still, this could be useful in the event of a germ warfare attack, a tuberculosis outbreak or in a patient who has an infection that simply doesn't respond to antibiotics. Of course, we won't know whether it works at all in people until researchers put that to the test. That's the next step - and a big one.

Richard Harris, NPR News. Transcript provided by NPR, Copyright NPR.