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�����ջ� Biologists Isolate Virus That Preys On Deadly Germs

Newly discovered bacteriophage destroys drug-resistant strains of E. coli.

�����ջ� students working with Prof. Jay Mellies have developed a virus that attacks deadly strains of E. coli bacteria responsible for millions of cases of every year. With antibiotic resistance becoming increasingly widespread, the discovery of the virus—known as PDX—points the way towards a new therapeutic strategy in which the pathogen’s game plan of attacking a host from within is effectively turned against it.

The team’s , reported in the preprint journal bioRxiv, reveal that PDX is a lethal saboteur when it comes to killing two deadly strains of bacteria, enteropathogenic (EPEC) and enteroaggregative (EAEC) E. coli. The team used host susceptibility assays, transmission electron microscopy, and genomic analysis to confirm that PDX shows strong “bacteriolytic activity”—in lay terms, it kills bugs dead.

PDX belongs to a family of viruses known as bacteriophage (phage for short) which prey exclusively on bacteria. Phages are incredibly common—according to one estimate, there are roughly 10^31 phages on the planet. If they were all stacked end to end, they would form a tower approximately 220 million light-years tall. “They’re literally everywhere,” says Prof. Mellies.

Leah Cepko ’16 became fascinated by phage after taking a class in microbiology with Prof. Mellies. “I loved that class,” she says. “For my thesis, I wanted to see if we could find a phage that targeted EPEC, which is the organism that Jay works with.”

The hunt began at a municipal wastewater treatment plant in North Portland. Donning a sturdy pair of gloves, Leah stuck a 1-liter nalgene bottle on a pole, and gingerly lowered it into a giant vat of sewage. “It was amazing,” she says. The wastewater was teeming with bacteria, of course, but it was also swarming with phage. After filtering out the impurities, she began a long series of steps to isolate phage that might target EPEC by injecting samples into petri dishes laden with the lethal germ, and then waiting to see if any of the dishes developed plaques—tiny dots indicating that the phages had successfully attacked the colonies of EPEC.

One morning in the fall of 2015 she got up early and rushed down to the lab. “I was praying for plaques,” she says. “I actually walked down the hall singing about plaques. I remember opening the incubator door—it was so dramatic—and seeing the plaques and being amazed. It was insane!”

PDX is a species of myovirus, a distinctive family characterized by icosahedral heads and spindly tails that attach to the cell wall of their bacterial target. Once attached, the phage punctures the wall like a syringe and injects its DNA into the hapless bacterium, essentially hijacking its host’s cellular machinery for its own reproduction. The bacterial cell eventually collapses, releasing a flood of new phages to seek fresh targets.

Phage therapy is not a new idea. The godfather of phage, French-Canadian biologist  published his first paper in 1917 and went on to pioneer phage therapy in the USSR, but his work was not widely accepted in the US and Europe, where doctors were more excited about antibiotics. D’Herelle died in 1949 and research into phage therapy ground to a halt for decades—until the emergence of drug-resistant bacteria spurred renewed interest in the approach.

One key advantage of phage therapy is that it can be tailored to a particular strain of bacteria, unlike antibiotics which are the “carpet-bombers” of the microbial world, decimating broad swathes of healthy bacteria as well as harmful ones. PDX has another advantage, too—it’s lytic, not lysogenic, meaning that its genetic material does not get tangled up with the DNA of its bacterial prey, lengthening the odds that the bacteria will undergo dramatic mutation.

Since 2015, �����ջ� biologists including Madeline Dinsdale ’17, Eliotte Garling ’18, William Scott ’19, and Loralee Bandy ’20 have been working hard to understand the biochemical mechanisms behind PDX and explore its potential as a treatment for deadly E. coli infections.

Meanwhile, Leah is pursuing a PhD in microbiology and genetics at Harvard, where she is currently researching the genetics of the bacterial pathogen Francisella tularensis, which causes tularemia. 

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