Microkillers

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 from Texas a&m University in the us. 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 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.

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 3-10 genes, could escape from their hosts. Small phages lack the genetic machinery needed to manufacture endolysins the way large ones do.The thousand dollar question has been how they made bacteria blow up.

Young's group looked at two different phages inhabiting Eschericha 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 Eschericha 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, which attacked a different step in the cell-wall synthesis. They are currently investigating a third virus that may inhibit yet another stage of cell-wall development, says Young.

The diversity in the way phages get out of their hosts shows there are many options for developing phage antibiotics. 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 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.

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 (www.techreview.com , 15 August).

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