Turning DNA into an antibiotic.

Hoping to alleviate the desperate need for novel antibiotics, investigators are turning to DNA as a potential weapon in the ongoing war against bacteria. Paul F. Agris and his colleagues at North Carolina State University in Raleigh have successfully modified a small strand of DNA to mimic and interfere with a vital cog in the machinery that bacteria, yeast, and mammalian cells use to make proteins. "It could be the forerunner of a new type of antibiotic," says Agris.

The journey from a gene to the protein that the gene encodes starts when a cell's nucleus creates a molecule known as messenger RNA (mRNA) from the gene's DNA sequence. While DNA is composed of two intertwined strands of complex molecules called nucleotide bases, mRNA consists of a single string of such bases.

Completed mRNA molecules leave the nucleus for parts of the cell known as ribosomes. There, molecules of another form of RNA, short strands called transfer RNA (tRNA), briefly hook up to the ribosomes. They decode the sequence of bases in the mRNA and help chemically link the appropriate amino acids to form the gene's protein. The two tasks are carried out by different parts of the ribosome, however. "The large subunit is where the chemistry occurs. The small subunit is where the decoding occurs," says Agris.

As part of an effort to understand how tRNA attaches to the small subunit of a ribosome, Agris and his colleagues began to design DNA strands that resemble tRNAs in structure. "We chose DNA because it wasn't that far off from RNA," says Agris. To find a DNA sequence that would attach to ribosomes as a tRNA would, the investigators had to create an RNA-DNA chimera. For example, they added to their DNA a nucleotide base normally used by RNA but not by DNA.

Because these chimeras compete with tRNAs for binding sites on the small subunits of ribosomes, they interfere with protein assembly. In fact, adding these mimics to cells cut the protein production by 50 percent, Agris and his colleagues report in the January Nature Structural Biology.

If investigators can modify the tRNA mimics further, so that they shut down the protein construction only in fungi or bacteria and not in human cells, the molecules may provide an extremely useful antibiotic, says Agris. Many current antibiotics, he notes, interfere with the stringing together of amino acids by attacking the large subunit of ribosomes. Antibiotic resistance often develops, however, because the shape of the large subunit can mutate easily. "It denies the antibiotic a binding site," says Agris.

He and his colleagues suggest that their approach may prevent the development of antibiotic resistance. "By targeting the small subunit, we're probably at a location where resistance cannot occur," asserts Agris. "You can't change something so universal to the organism as the decoding process."

The investigators are also studying whether they can use liposomes, spherical globules of fat, to deliver their DNA-based tRNA mimic into cancer cells but not healthy cells. By halting protein assembly, the compounds would kill the cancer cells.