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 flagella 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 firstname.lastname@example.org.