Tiny bacterial parasites could serve as models for drugs effective against antibiotic-resistant bacteria, providing another line of defense against the threat of incurable diseases.

The bacterial viruses, or bacteriophages, produce proteins that prevent bacteria from building an outer cell wall, reported researchers at Texas A&M University in the June 22 issue of Science. This disruption of the cell wall weakens and ultimately kills the bacteria cell.

The discovery of this bacteria-killing mechanism in the smallest viruses is a “milestone in our quest for antibiotics,” says Dr. Sankar Adhya, chief of developmental genetics at the National Cancer Institute in Bethesda, MD. The simplicity of the mechanism suggests a quicker route to designing new antibiotics that can continue to be effective against bacterial resistance.

The Walls Come Tumbling Down

Researchers have long known that phages with larger genomes break out of bacterial cells with the help of an endolysin-an enzyme that enables them to rip through cell walls. But it remained a mystery how smaller viruses, with only three to 10 genes, could escape from their hosts.

Small phages lack the genetic machinery needed to manufacture endolysins the way large ones do, says Ryland Young, who led the Texas A&M research team. “We wanted to know how [they] made bacteria blow up.”

Young’s group looked at two different phages inhabiting E. coli bacteria: Q-beta and phi-X174. In both they cloned the single gene they knew to be involved in the virus’s exit from its host. After injecting the gene into live E. coli, they found that only a few rare mutants managed to survive.

On a closer look, they found the injected gene had been altered in the mutant bacteria. And this allowed them to pinpoint the exact step in the process of cell-wall synthesis that each phage was inhibiting.

Although the Q-beta and phi-X174 viruses both inhabited the same host, the researchers found that each made a protein that attacked a different step in cell-wall synthesis. They are currently investigating a third virus that may inhibit yet another stage of cell-wall development, says Young.

Designing New Antibiotics

The diversity in the way phages get out of their hosts “shows there are many options for developing phage antibiotics,” says Graham Hatfull, a microbiologist at the University of Pittsburgh.

Phage DNA could be used to produce protein antibiotics that would attack bacterial cell-wall synthesis at any one of several steps in the process. This versatility, Young explains, would make the antibiotics more readily adaptable to new strains of bacteria.

In theory, when bacterial strains develop resistance, manipulating the DNA code to attack a different point in the cell-wall armor is an easier and quicker strategy than attempting to revise the complex molecular chemistry of a synthetic antibiotic.

“Can you imagine making something with 47 carbon atoms and six different rings?” says Young. “It’s very difficult and expensive to change an existing antibiotic.”

Furthermore, the bacterial cell wall is an opportune target for antibiotics because human cells don’t have an outer wall, so phage antibiotics should not have harmful side effects.

But designing antibiotics that attack bacterial cell-wall synthesis is still problematic in that the pathway is nearly universal in bacteria. A successful antibiotic could prevent cell-wall formation in beneficial bacteria too, says Vince Fischetti, a phage specialist at Rockefeller University.

Other Phages

In addition to the design of new antibiotics, researchers are exploring other ways of tapping the anti-bacterial arsenal of phages.

Working with larger phages, Fischetti’s research team at Rockefeller University will soon begin clinical trials of inexpensive “enzyme sprays” that could destroy bacteria within a few hours. Up to 50 percent of hospital patients, for example, carry infectious pathogens like pneumonia in their nose and throat, says Fischetti, who thinks that the sprays can bring that level down to as low as one percent.

“The sprays are not really curing [bacterial infection] but inhibiting it altogether,” explains Fischetti. Enzyme sprays could also be used in the food industry to decontaminate food, he says.

Phage therapy is another approach to combating bacterial diseases. In this method, live phages are used to attack the infection. The advantage is that live phages multiply exponentially, like bacteria. A small initial dose will spread through bacteria cells, meaning that repeated doses aren’t necessary.

First tried as early as the 1930s, phage therapy lost favor after the invention of penicillin and other antibiotics. Only in recent years has interest in it resurfaced with the alarming spread of antibiotic-resistant bacteria and the associated threat of incurable diseases, says Adhya.

Two companies-Phage Therapeutics in Bothell, WA, and New York-based Exponential Biotherapies-are currently in pre-clinical and clinical trials of phage-based therapies to combat bacterial infections.