Viruses to the Rescue?

Last week, a paper in Nature Medicine described a British teenager whom doctors pulled back from the brink of death. The young woman had developed a deadly, antibiotic-resistant infection following lung surgery. The treatment? Phage therapy, in which viruses are used to kill dangerous bacteria. This novel approach made headlines around the world. Let’s look at the science behind phage therapy for antibiotic-resistant bacteria.

Term of the Week: Bacteriophage

A bacteriophage—also referred to as a phage—is a virus that infects bacteria. By attaching to the microbe’s surface, a phage punches holes in the membrane and injects its own genetic material. The intruding phage replicates, creating so much new virus that the bacterium explodes. A slew of fresh viruses infect other bacteria, wiping out the population.

The word “bacteriophage” comes from the Greek word phagein—“to devour.” These ravenous microbes often have a taste for the bacteria that can kill us.

Typically a phage ”partners” with only one type of bacteria. They’ve coevolved for millennia, each adapting and changing in response to the other. That’s key. It means that we’re much less likely to develop “phage resistance”—as we have to many antibiotics.

So when researchers tweak a bacteriophage for therapeutic use, they select one that will attack only nasty bacteria. This remarkable precision leaves many strains of “friendly” bacteria that comprise our gut microbiome alone. Humans have safely coexisted with bacteriophage literally for ages, which suggests the viruses pose only a minimal safety risk.

We’ve known about the bacteria-devouring ability of phage for about a century. However, the seemingly miraculous advent of antibiotics in the late 1920s shifted medicine’s focus to the new wonder drugs. Antibiotics were much easier to manufacture and test in controlled settings.

The alarming emergence of antibiotic resistance has renewed interest in these killer viruses, which are for the first time starting to be manufactured and tested in a standardized way. Here are some biotech companies delving into the promising world of bacteriophage-based therapeutics. (Article continued below.)

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The Virologist-Mixologists Get Busy

The first multicenter clinical trial examining bacteriophage as antibacterial treatments was initiated in 2015 by French biotech Pherecydes (Paris, France). Since bacteriophage are an entirely new type of biologic drug, the researchers had to establish production protocols to meet good manufacturing practice guidelines.

The scientists are studying two viral “cocktails”—mixtures of different bacteriophage that have shown activity against different substrains of a particular bacteria. The first contains 13 phages targeting P. aeruginosa; the second, 12 phages that target E. coli. The company is evaluating them against burn wound-associated infections. The company is also on the cusp of clinical trials of phage therapy to treat diabetic foot ulcers infected by S. aureus.

Other companies testing phage cocktails include:

  • AmpliPhi Biosciences (Richmond, VA): Phage cocktail AP-SA01 is now in Phase II clinical testing for antibiotic resistant Saureus against chronic rhinosinusitis and acute, chronic wound and skin infections. Additional targets include bacteremia, endocarditis, prosthetic joint infections, osteomyelitis, and diabetic foot ulcers.
  • TechnoPhage (Lisbon, Portugal): Phage cocktail TP-102 is in Phase I studies for bacteria associated with chronic ulcers.
  • Intralytix (Baltimore, MD): Completed Phase I studies of a bacteriophage to treat infected wounds. The company is also developing phage-based biologics to fight food-borne pathogens. Its EcoShield targets coli, and SalmoFresh, salmonella.
  • EpiBiome (South San Francisco, CA): Phage cocktails targeting Ecoli and S. dysenteriae diarrheal infections are in preclinical development.

The Bioengineers Take a Whack

Creating a phage cocktail is challenging. Happily, it’s also possible to genetically engineer a synthetic virus that combines the desired properties of multiple phages into a single genome.

For example, scientists can insert genes into a phage genome that increases the range of bacteria subtypes an individual phage can attack, while maintaining the specificity that prevents it from turning on benign bacteria. Researchers could also add genes to further amplify the bacteriophage’s antibacterial response. Companies with engineered bacteriophage in preclinical development include Synthetic Genomics (San Diego, CA) and EnBiotix (Cambridge, MA).

Lysins in Wait

A third approach to harnessing the therapeutic power of bacteriophage lies in isolating what makes them toxic. For example, to inject their genome into bacteria, phage must essentially bash holes in their membranes. This blow is itself very damaging to bacteria. The viral protein that creates these tears are lysins—enzymes that essentially chew holes in the bacterial cell wall. ContraFect (Yonkers, NY) is conducting Phase II clinical studies of its drug CF-301—a lysin—to treat S. aureus bloodstream infections.

Snip Snip!

Locus Biosciences (Morrisville, NC) identifies bacteriophage that target specific strains of bacteria and engineers them to deliver CRISPR components to those bacteria, including guide RNA and the Cas3 protein. The guide RNA directs the Cas3 protein to cut up the bacterial DNA.

For CRISPR genome editing, the Cas9 protein is used. Cas9 cuts target DNA in a single, precise location. Cas3 chews up target DNA much more thoroughly than Cas9, making it a better choice for destroying a bacterium. Locus plans to enter clinical trials in 2019 with phage treatment for urinary tract E. coli infections.

Although still in its early days, bacteriophage therapy offers the possibility of a safe, effective and intriguing solution to one of the major public health crises of our time.

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