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How bacteria-eating bacteria could help win the war against germs

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Katherine J. Wu, The New York Times

<div class="embed-wrap"><figure data-feedback="fb:likes,fb:comments"><img src="http://sa.kapamilya.com/absnews/abscbnnews/media/2020/tnyt/08/27/bacteria.jpg"/><figcaption>In an undated image from Julia Johnke, Matthias Schmidt and Nedal Said, small, comma-shaped Bdellovibrio bacteriovorus enters its prey, the larger E. coli. Julia Johnke, Matthias Schmidt and Nedal Said via The New York Times</figcaption></figure></div>NEW YORK - Henry N. Williams’ favorite movie-action sequence unfolds on a strip of glass just a few millimeters across.It’s a cinematic showdown between two bacterial cells: Vibrio coralliilyticus, a large, rod-shaped marine microbe, and a petite pursuant, Halobacteriovorax, that has latched onto the bigger bacterium. The Vibrio, desperate to jettison its assailant, wriggles and whirls through a pool of liquid, zigzagging in futility before finally coming to a “screeching halt,” as Williams described it.Then the Halobacteriovorax starts its dirty work: It punctures the Vibrio’s exterior and begins to bore inside, where it will gorge on its host’s innards, clone itself many times over and burst free to find its next meal.Williams, a microbiologist at Florida A&amp;M University, delights in showing students these videos of so-called predatory bacteria, a loose group that includes Halobacteriovorax and a bevy of other microbial assassins. The bacteria never fail to impress.“It engenders a lot of ‘wow’, a lot of ‘oh my goodness’,” he said. “Lions, sharks, tigers — these are all predators that have gotten our attention. But there also exists a much smaller predator that is just as ferocious.”Predatory bacteria carry immense promise in an extraordinarily small package. Deployed under the right circumstances, they could help people beat back harmful microbes in the environment, or purge pathogens from the food supply. Some experts think they could someday serve as a sort of living therapeutic that could help clear drug-resistant germs from ailing patients in whom all other treatments have failed.But even the small community of researchers who study predatory bacteria have not fully figured out how these cells select and slaughter their hosts. Teasing out those answers could reveal a range of ways to tackle stubborn infections, and provide a window onto predator-prey dynamics at their most microscopic.To potentially use this group of microbes as “a living antibiotic, we need to know how it grows,” said Terrens Saaki, a microbiologist studying predatory bacteria at the de Duve Institute in Belgium. “We can’t use it if we don’t understand it.”<div>Tiny terrors</div>Predatory bacteria were discovered by accident. Scientists stumbled upon them more than a half-century ago while hunting for another type of murderous microbe called a bacteriophage, or phage, a virus that can infect and kill bacteria. Before then, Williams said, “it was not known that a bacterium would prey on other bacteria in this fashion.”That predatory bacteria eluded detection for so long is somewhat surprising. Many dozens of species teem in the seas and in clods of dirt. They are thought to be hardy enough to weather animal guts, including our own, and seem to persist everywhere from raw sewage to the gills of crabs.“My students have isolated them from soil, from snails in freshwater streams, from the drain in a custodial closet down the hall from our lab,” said Laura Williams, who studies predatory bacteria at Providence College in Rhode Island (and is not related to Henry Williams). “Anywhere there are bacteria, there are probably predatory bacteria trying to eat them.” And scientists are identifying more of these predators each year — a striking parallel to the world’s diversity of phages.But phages and predatory bacteria are very different beasts. Phages tend to target a narrow range of hosts, whereas many predatory bacteria are far less finicky. Some predatory bacteria are amenable to eating dozens, if not hundreds, of bacterial species, enabling them to thrive in most habitats. And whereas phages work quickly, massacring entire populations within hours, predatory bacteria are plodding, sometimes taking weeks to grow in the lab.And while other microbes are content to feast on nutrient-rich broth, predatory bacteria demand a steady supply of live prey.“It’s a pain in the —” said Julia Johnke, a microbiologist studying predatory bacteria at the University of Kiel in Germany.Still, their predatory lifestyle is so fruitful that it appears to have evolved more than once. Some, such as the leechlike Micavibrio, grab onto their victims like vampires and suck them dry. Others, like Myxococcus, are sharpshooters that operate from afar, releasing a deluge of enzymes that can dissolve their prey at a distance. Some Myxococcus cells even band together to hunt, attacking in a coordinated swarm.Perhaps the most notorious of the bunch, a group called Bdellovibrio, shares a modus operandi with Halobacteriovorax: They penetrate their hosts and annihilate them from within. Most predatory bacteria experts call these perforating predators BALOs, an acronym for Bdellovibrio and like organisms. (At least one Bdellovibrio — called Bdellovibrio exovorus — chose the vampiric path instead.)As a whole, predatory bacteria are “very efficient killing machines,” said Daniel Kadouri, a microbiologist at Rutgers University who has been studying predatory bacteria since 2003. “The first time I saw them, I thought, ‘These are the sexiest organisms I have ever seen.’”<div>Living therapeutics</div>Once a bacterial predator has homed in on its prey, little can stop it. Whereas antibiotics and bacteriophages tend to target very specific parts of a bacterium’s anatomy, bacterial predators are blunt agents of gluttony: A microbe can no more easily evolve resistance to them than a rabbit can evolve resistance to a wolf.Even before latching onto their prey, BALOs are formidable foes, capable of chemical sensing that allows them to “sniff” out their prey and then give chase, propelling themselves forward by rotating a corkscrewlike tail called a flagellum. “They can swim 100 times their body lengths in a second,” Kadouri said. “Pound for pound, that’s faster than a cheetah.”In animal studies, predatory bacteria have shown promise in targeting disease-causing germs like Salmonella and Yersinia pestis, which causes the plague. Kadouri and Nancy Connell, a microbial geneticist at the Johns Hopkins Center for Health Security, have dosed Bdellovibrios into the lungs of rats and mice and watched them devour most of the prey at hand. Trials in chickens and zebrafish have yielded encouraging results as well.Notably, predatory bacteria have no interest in nonmicrobial cells, and don’t seem to agitate the immune system — even when applied directly onto the surface of a rabbit’s eyeball. This suggests that these microbes could be safe for use in people, Kadouri said: “We’ve shoved quite a lot of predator bacteria into animals and never saw an aggressive immune response.”But these predators flourish only in the presence of their prey, so they typically struggle to vanquish entire populations of microbes on their own. And being microbes, they too will eventually be swept out of the body by immune cells, against which they have “absolutely no defense,” Connell said.As a result, predatory bacteria are not strong candidates for treating infections that have already spread throughout the body. Administered in the right way, however, predatory bacteria might be coaxed to work in concert with the immune response to eliminate their targets. They could also be partnered with another therapeutic like an antibiotic or even a light dose of phage.“We need to start thinking about holistic approaches,” Kadouri said. “It’s another tool in the arsenal.”With further study, predatory bacteria could someday change “how we give basic care,” said Saaki, who hopes to bring more accessible medicine back to his home country of Suriname.<div>Restoring order</div>Predatory bacteria are not exclusively weapons of destruction. In Germany, Johnke is at work on a series of projects that highlight the microbes’ peacemaking skills in the complex community of bacteria that live in the gut.Some evidence suggests that “healthy human beings usually have predatory bacteria as part of their microbiome,” she said. Little is understood about their role, she added. But they likely maintain order in the gut and ensure that no single species runs amok.Johnke’s work suggests that people with gastrointestinal disorders like Crohn’s disease may have lost this delicate balance. Reintroducing predators to the ecosystem might help restore it. “In my ideal world, we could use BALOs as some sort of probiotic,” she said.A similar dynamic likely holds true out in nature, where Henry Williams, of Florida A&amp;M University, has turned most of his attention. Even tiny amounts of predatory bacteria can completely rejigger the microbial membership of a sample of seawater. “They’re always present, managing the population of some bacteria,” he said.Many microbiology textbooks contain a nod to the importance of predators like phages and protists, a group of mostly single-celled microbes whose cells resemble those of animals. But predatory bacteria have largely been left out, even though they appear to be at least as effective at taming their prey. That perhaps makes these microbes some of the world’s least visible underdogs. “It’s been hard to get people to take them seriously,” Williams said.<div>Microbial mysteries</div>Even if no widespread therapeutics come of predatory bacteria, they are, to experts, gems of basic biology.In Belgium, Saaki and his adviser, Géraldine Laloux, are trying to understand how Bdellovibrio grows and divides inside other bacteria. “You don’t see that very often,” Laloux said.Typical bacteria replicate by briefly elongating, then cleaving themselves in two. Bdellovibrios, in contrast, will spool themselves out into long, spaghettilike strands, then segment themselves into multiple daughter cells, like an assembly line of sausage links. “There are up to 16 of them in some cases,” Laloux said. The entourage will then exit the host cell en masse, about four hours after the parent Bdellovibrio first made contact.“That is totally different from what we know about how bacteria proliferate,” Laloux said. She added that this supercharged reproduction strategy might be a way for Bdellovibrio to cash in while it can. “Once you are in there, you are protected from the environment and harsh conditions,” she said. “Maybe you want to get the most out of it.”Across the Atlantic, Laura Williams of Providence College is studying “the other side of the coin” — the prey. Each predatory bacterium has its own array of targets, but it’s unclear how much that owes to the pickiness of the predator or to the resilience of the prey. Her students have gathered some evidence that certain E. coli strains might be a tougher swallow than others, for reasons still unknown.Some of those mysteries will be for the next generation of predatory-bacteria enthusiasts to solve. A thousand or so miles south, in Florida, Henry Williams often thinks back to when he first heard of the microbes, during a graduate school seminar five decades ago. He now gives the same energizing talks to a new crop of students, he said: “I still find them just as exciting as I did on day one.”

Predatory bacteria carry immense promise in an extraordinarily small package. Deployed under the right circumstances, they could help people beat back harmful microbes in the environment, or purge pathogens from the food supply.

Predatory bacteria carry immense promise in an extraordinarily small package. Deployed under the right circumstances, they could help people beat back harmful microbes in the environment, or purge pathogens from the food supply.

How bacteria-eating bacteria could help win the war against germs

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How bacteria-eating bacteria could help win the war against germs

Katherine J. Wu,

The New York Times

Published Aug 27, 2020 11:50 AM PHT

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