Bdellovibrio, the cannibalistic drug coming to humanity’s rescue | Ars Technica

Bdellovibrio, the cannibalistic drug coming to humanity’s rescue | Ars Technica

Bdellovibrio isn’t your average kind of bacteria.

“It has a psychological problem,” jokes Robert Mitchell, a microbiologist and an associate professor at the Ulsan National Institute of Science and Technology in South Korea. “It thinks it’s a virus.”

Though it may have an identity crisis, Bdellovibrio has managed to spread to a wide range of environments, including soil, bodies of water, animals, plants, and humans. And its unique set of oddities has made it rather appealing to researchers, many of whom have realized its potential utility—biomedically, industrially, even environmentally.

Scientists are exploring all sorts of ways to use these Bdellovibrio, largely inspired by its rather strange life cycle. Typically, bacteria work pretty simply. Once they get to an environment with useful nutrients, they spend some time preparing for growth and then they reproduce. Their reproduction is rapid and usually accomplished via binary fission: they split themselves, forming two identical clones.

But Bdellovibrio is parasitic; it reproduces by attacking other bacteria. “It can only finish its life cycle by preying on other bacteria,” says Daniel Kadouri, an associate professor in the Center for Oral Infectious Diseases at Rutgers University. First, the bacterium attaches to the outside of a bacterial cell and drills a hole through the outer membrane. It then enters the cell and begins dissolving and consuming the host cell’s proteins and nucleic acids. “It sits between the inner and outer membranes and starts secreting enzymes that will basically break down the prey from the inside,” Kadouri told Ars. Finally, after feeding on its prey, dividing, and producing multiple progeny, the bacteria burst out of the host cell, tearing it apart in the process.

And Bdellovibrio is very efficient in all this. According to Kadouri, “From one Bdellovibrio bacterium coming in, you can get several coming out.”

So what exactly does science want with a bacteria that eats other bacteria better than any other? Plenty.

Accidental answer

The strange Bdellovibrio and its predatory ways were discovered by accident. In 1962, researchers Heinz Stolp and Heinz Petzold made two mistakes. First, while filtering soil for viruses, the two ran out of the right sized filters. They used a different kind that had much larger pores, and this let some Bdellovibrio through.

Once Stolp and Petzold had filtered their soil samples, they tested the filtered part for viruses by culturing it in a petri dish filled with bacteria. If after 24 hours no sign of viral infection had appeared, the protocol was to trash the samples. And after they used the larger filter, the soil sample showed no viral growth after a day—yet for some reason, they didn’t throw it out. Three days later, they tested it again and found something that was acting a lot like a virus would. That something was Bdellovibrio. Stolp and Petzold only found it because the larger pore filters allowed Bdellovibrio to get through.

Since then, researchers have learned a lot about the organism’s lifestyle, recognizing that it could prove useful in a number of ways.

One big way Bdellovibrio could help us out is in the fight against multidrug-resistant bacteria. Increasing numbers of bacterial strains are becoming difficult to fight with traditional drugs. With few options left in our toolbox, researchers are looking at non-traditional ways to combat them. And because Bdellovibrio feeds on other bacteria, it makes an appealing alternative to antibiotics.

When discussing the development of drug-resistant bacteria, Kadouri told Ars, “They were always there, but we always had good drugs to treat them with. The bacteria didn’t learn a new trick. They mutate and evolve. That’s what they do.” The problem today is that we put the bacteria in a position that forced them to mutate very rapidly. “What we’re doing is we’re submerging the environment with so many antibiotics, we’re speeding up the process of natural selection,” says Kadouri. And our overuse of antibiotics isn’t limited to hospitals and hand sanitizer. As Kadouri points out, 80 percent of our antibiotics are used in agriculture.

Not only are we pushing these bacteria toward drug resistance, we’re not producing new antibiotics to fight them rapidly enough. “When pharmaceutical companies develop a drug for a chronic disease, people are going to be taking that drug for 40 or 50 years. Whereas with antibiotics, you’ll be taking them for five days and then within two years, the bacteria will become resistant,” says Kadouri. “So where’s the return in investment? It’s kind of the perfect storm.”

But using Bdellovibrio in conjunction with or instead of antibiotics seems to be a viable option. Scientists have tested it against two classes of bacteria (gram-negative and gram-positive) to see how well it fares against them.

Research has shown that many types of gram-negative bacteria fall as prey to Bdellovibrio, which is a gram-negative bacterium itself. But prior to 2013, it wasn’t known how well the bacteria preyed on multidrug-resistant strains of gram-negative bacteria. Kadouri and his team selected 14 different multidrug-resistant strains, using those typically found in a clinical setting. They then tested how well Bdellovibrio brought down the viability of the bacterial strains.

Two different Bdellovibrio strains turned out to be highly effective at reducing the viability of the 14 tested strains, regardless of their resistance to antibiotics. But the fact that we had to do this work at all highlighted what we don’t know—why does Bdellovibrio prey on some bacteria and not others? “To this day, not much is known about the biology of these organisms,” says Mitchell. “We don’t know how they recognize their prey.”

Biofilm bully

Thus far, research has proven that Bdellovibrio can prey on gram-negative bacteria, but it can’t target gram-positive strains. This is another thing we can’t really explain yet. But as Mitchell has shown, that doesn’t mean it’s ineffective against gram-positive infections. Bdellovibrio can do useful work by targeting their neighborhood.

Many microorganisms, like bacteria, tend to stick to each other and to a surface, forming what’s known as a biofilm. “A biofilm is a community of bacteria,” says Mitchell. “They attach to surfaces by secreting proteins, DNA, and extracellular polysaccharides [complex sugars], and they form this network, like a mesh, which helps them to stably adhere to a surface.” Mitchell says that an example he uses with his students is the film you can scratch off of your teeth. That’s a biofilm formed by bacteria from the food we eat. And though Bdellovibrio won’t feed on or kill gram-positive bacteria, it can break up biofilms they live in.

Bacteria that form biofilms are generally more resistant to antibiotics than those that don’t. And one place where these biofilms are a big problem is in hospitals, which have lots of surfaces that can play host to biofilms. The Centers for Disease Control and Prevention estimates that about one in 25 patients contracts an infection while in the hospital, an event the CDC refers to as healthcare-associated infections.

Staphylococcus aureus is a multidrug-resistant, gram-positive bacteria that causes some of the most problematic healthcare-associated infections. Not only does it form biofilms on the skin and the nose, it can form them on non-biological surfaces like medical equipment and implants.

“As much as 30 percent of the population has Staphylococcus aureus inside their nose, but it doesn’t cause problems for many people,” says Mitchell. “But it does become a problem specifically in the hospital where you have patients who are immuno compromised. Or their immune system is already being battered by other infections or diseases and suddenly they’re being exposed to this multidrug-resistant organism where it can now cause problems.”

Although Bdellovibrio can’t prey on Staphylococcus aureus (it’s gram-positive), it does produce a huge amount of proteases, enzymes that can break down the secretions that attach the biofilm bacteria to surrounding surfaces and to each other.

Mitchell and his fellow researchers looked at how the bacteria’s enzymes, including proteases, affected Staphylococcus biofilm formation. They found that, though Bdellovibrio didn’t halt Staphylococcus aureus growth, it did prevent biofilm formation. It also broke up already formed biofilms and, importantly, reduced the bacteria’s ability to invade human cells. Mitchell told Ars, “It had this unexpected effect in that it chewed up the surface proteins of the pathogen, reducing its ability to invade human cells.”

Kadouri sees a future for fighting bacteria that’s much different from our current practices. “Physicians don’t like to mix therapeutics, and pharmaceutical companies hate it because then they need to do efficacy and toxicity experiments for each one of the elements. But we’re going to be in a position that we’ll have to start mixing.” As an example, Kadouri suggests that we could use predatory bacteria like Bdellovibrio to knock out the biofilm first and then come at the problem bacteria with the antibiotics. He points out that doing this would put less selective pressure on the bacteria and could slow down their evolution, keeping the bacteria from developing resistances too quickly.

“Do we need to reduce the invading bacterial population by 100 percent or can we reduce it by some and let the immune system take over?” Mitchell wonders. Whatever the approach becomes, it’s clear that sometime soon our strategies will have to take a necessary shift.

A parasitic punch to the gut

While multidrug-resistant bacteria and biofilm formation are rightly at the forefront of our concern, Bdellovibrio is also being used in a number of other ways. When it comes to health, researchers are also investigating ways to use Bdellovibrio internally, like in the gut.

The gut contains a ton of bacteria, and the gut microbiota makeup has recently been connected to depression, autism, and even multiple sclerosis. In a 2013 PLOS ONE study, researchers in Italy found a correlation between the presence of Bdellovibrio in the gut and gastrointestinal disease. While healthy individuals all had Bdellovibrio living in their intestines, its abundance was significantly reduced in patients with Crohn’s disease or Celiac disease. The authors hypothesized that predatory bacteria like Bdellovibrio may serve as population balancers, keeping unhealthy bacteria in the gut in check. If so, it could be a treatment option for Crohn’s or Celiac patients.

A paper published this past March explored a similar idea: that the loss of diversity within the gut microbiota may have severe effects on our health. The authors looked at the idea of rebiosis, or the restoration of microbial diversity, using, among other things, Bdellovibrio. But as Alexis Mosca, an author of the paper and a physician at the Robert Debré University Hospital in Paris, France, notes, there’s still a lot we don’t know, both about gut microbiota and predatory bacteria like Bdellovibrio. “We don’t know the role Bdellovibrio plays in the gut, and we don’t know its function in shaping the gut microbiota,” Mosca told Ars.

Mosca also points out that the bacteria only exist in very small numbers in this environment. But he hypothesizes that it’s still possible Bdellovibrio and other predatory bacteria might play a part in managing the diversity of gut microbiota.

Of course, any talk of using Bdellovibrio to combat bacteria inside of someone has to include a discussion of any potential negative effects Bdellovibrio may have in our bodies. Says Kadouri, “If the technology isn’t safe, we’re dead in the water.”

In that vein, Kadouri’s lab looked at how the bacteria affected immune responses in mice both when administered intranasally or directly into the bloodstream. They found that in both cases the immune response was low—some inflammation, some increases in cytokines—but minor changes that lasted less than 24 hours. And the bacteria itself worked its way out of the mice quickly. In fact, over the course of four years of research, “we never lost an animal to predatory bacteria,” says Kadouri.

Since we know Bdellovibrio does a good job at battling certain bacteria in vitro, we now need to test how well Bdellovibrio battles bacteria in vivo. “The next step would be to see if we can use it to clear an infection,” Kadouri told Ars, hinting at upcoming work.

From health to harvests

Even as researchers are trying to get a more complete picture of Bdellovibrio’s use for health, others are finding its utility extends further. For example, it may be possible to use Bdellovibrio to harvest bioproducts from other bacteria.

Some bacteria store energy through the production of polymers called polyhydroxyalkanoates, or PHAs. As it turns out, PHAs are really good alternatives to petroleum-based plastics. They’ve been used to make everything from paint binders and adhesives to food coatings and medical sutures. The problem is that harvesting PHAs from the bacteria that produce them is pretty costly and can damage the PHAs.

But biology may provide us with ways of gently liberating these polymers. Some teams have used proteins from viruses that are responsible for breaking down cell membranes during infections. This releases PHAs from bacteria, but it isn’t applicable to a broad range of bacteria.

However, a study published this April in Scientific Reports found that Bdellovibrio could be used to accomplish the same thing. The researchers mutated Bdellovibrio to keep it from digesting the PHAs itself. “It likes to eat the polymer,” says Auxiliadora Prieto, a researcher at the Centro de Investigaciones Biológicas-CSIC in Spain and an author of the study. When these mutants were used to infect PHA-producing bacteria, the researchers were able to harvest over 80 percent of the polymers quickly and efficiently.

The next steps for Prieto’s lab are to improve the process of growing enough Bdellovibrio and to make it more aggressive toward the PHA-producing bacteria. The harvesting process also needs to be tested at an industrial scale. To do this, Prieto says, “We need a company to invest money into developing the process. Industry needs to be brave and try to implement biological methods into their processes.”

A final example of the breadth of Bdellovibrio’s use comes from a May Scientific Reports study. In it, the researchers describe using Bdellovibrio to sort of clear out bacterial cells but leave their shells (membranes and cell walls) intact. The researchers intend to construct synthetic cells with the leftovers.

Typically, Bdellovibrio destroy the bacterial cells they prey on. “Normal Bdellovibrio are efficient and ferocious predators that consume almost all of their prey,” said Carey Lambert, a research associate at the University of Nottingham in the UK and an author of the study. But with a couple of gene deletions, Lambert and the research team were able to keep Bdellovibrio from destroying its preys’ cell walls. Instead, what was left behind were “ghost” cells that still had cell walls, membranes, and structure.

These “ghost” cells could be used to create synthetic cells with any number of properties. “If you can design a basic ‘minimal’ cell, then you can add various functions to it,” says Lambert, “such as efficient factories for enzyme production or biochemical cleaning, such as oil eating for clearing oil spills.”

These findings are surely just the beginning for such an interesting bacteria and a rather young field of research. “I think that the… research field in predatory bacteria is very small,” says Mitchell. “I hope more people will jump in and help push it forward.”

And as far as the biomedical aspects go, additional research will have to be followed up with clinical trials. It’s a process that will take time, so utilizing Bdellovibrio at its fullest potential is likely quite a ways away. Considering this odd little bacteria has only been on the radar for 50-odd years, who knows what other uses we’ll find by then.


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