Anthrax Destroyer

For nearly every bacterium on the planet, there are naturally occurring viral assassins. Known as bacteriophages, these diminutive agents penetrate their targets and then replicate inside with abandon. Within an hour of infection, the viral progeny explode out of the target, leaving behind a bacterial carcass as they troll for new hosts.

Now researchers are exploiting the phages' cell-bursting, or lytic, tactics to kill even the most dreaded infective agents, including Bacillus anthracis, an icon of bioterrorism angst.

Using molecular clues from their discovery several years ago of a lytic enzyme, PlyG, in a bacteriophage that targets and kills B. anthracis and a related microbe, microbiologist Vincent A. Fischetti of Rockefeller University, in New York City, and his colleagues deployed bioinformatics techniques to identify a related enzyme, designated PlyPH. They subsequently found that PlyPH retains its cell-bursting powers through a particularly wide range of pH and temperature (J. Bacteriol. 2006, 188, 2711). That persistence opens up possibilities for using the protein agent both for in-body therapeutic and environmental decontamination applications in the case of an anthrax attack, Fischetti's group says.

Perhaps more consequentially, suggests Joshua Lederberg, professor emeritus at Rockefeller and a 1958 Nobel Laureate for his work in bacterial genetics, "this may be a precedent for a whole family of new antibacterials. It is something you can try on any bacterial target."

Like many other lytic proteins from bacteriophages, PlyPH has an antibody-like end that binds to chemical motifs that are specific to the cell walls of its small set of target microbes. The proteins' other end bears an enzymatic "hole-puncher" that breaches the cell wall. When that happens, the cell's contents, which are under about 3 atm of pressure, burst out like champagne from a just-uncorked bottle.

PlyPH "is not an antibiotic, and it is not a vaccine," remarks Fischetti, adding that the lytic enzyme's differences from existing anti-infective agents could prove valuable. For example, to survive an anthrax infection, a person typically must begin antibiotic treatment within two days of infection. If antibiotic supplies are strained as they might be in a terrorist attack, early administration of phage lytic enzymes such as PlyPH could keep anthrax cell proliferation in check, thereby extending the treatment window.

Preliminary experiments with a mouse model of an anthrax-like infection indicate that PlyPH is safe to administer and can save almost half of the animals from their infections. What's more, Fischetti says, cells challenged by the lytic enzymes do not seem to develop resistance. For antibiotic-resistant infections, lytic agents could come to the rescue, the researchers conjecture.

This "will be another arrow in the quiver" for treating infections, says Ryland Young of Texas A&M University, who studies the molecular mechanisms by which bacteriophages puncture cell walls and membranes.

For a century, scientists have attempted to exploit bacteriophages as anti-infective agents, but the ascent of penicillin and other antibiotics a half-century ago, among other factors, overshadowed that movement. With the rise of bacterial resistance to conventional antibiotics, threats of bioterrorism, and growing fears of pandemics of unprecedented scope, new strategies for defeating microbes are in ever greater demand, researchers say.