In findings published online in two complementary papers in Nature, the research team describe the differences in an enzyme called RNA polymerase in bacterial cells as opposed to human cells. These differences provide potential new targets for drug design.

RNA polymerase is the key enzyme regulating the transfer of genetic information from DNA to RNA, said Dmitry Vassylyev, Ph.D., professor of biochemistry and molecular genetics and lead author of both papers. All living organisms use this enzyme to transmit the instructions stored in genes (DNA) to messenger RNA (mRNA), which in turn communicates those instructions to the cells.

Specifically, Vassylyev's team traced the similarities and differences between human RNA polymerase and bacteria RNA polymerase, painting a more complete picture of the structure of this essential enzyme.

Knowing how RNA polymerase differs in human and bacterial cells means antibiotics can be designed with a greater probability that they will interact with and kill bacteria, while leaving healthy human cells alone, Vassylyev said.

Vassylyev said that not only does this present a pathway for new antibiotics, it also should allow for existing drugs to be improved. Some antibiotics are very good at killing bacteria, for instance, but have a difficult time penetrating the cell membrane, rendering them fairly ineffective.

Vassylyev's detailed view of RNA polymerase provides a foundation for producing drugs that will efficiently enter cells, bind to the RNA polymerase and destroy bacteria without inhibiting the growth of human cells.

Vassylyev collaborated with Irina Artsimovitch of Ohio State University and Robert Laudick of the University of Wisconsin. The research was funded by the National Institute of General Medicine Sciences, one of the National Institutes of Health.

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"However, while TRIM5a may have served humans well millions of years ago, the antiviral protein does not seem to be good at defending against any of the retroviruses that currently infect humans, such as HIV-1," Emerman said. "In the end, this drove human evolution to be more susceptible to HIV."

For example, the researchers found that changes in TRIM5a that make it better at fighting HIV actually inhibit its ability to stop PtERV1 and vice versa, which indicates that this antiviral gene may only be good at fighting off one virus at a time.

Uncovering the story of TRIM5a's role in battling one ancient retrovirus while increasing human susceptibility to modern-day HIV "is a lot like doing archaeology ” figuring out how humans have become who we are today and why we are or are not susceptible to modern viruses that presently circulate," Emerman said.

In fact, this emerging area of research, which seeks to better understand modern infections by studying ancient viruses, is known as "paleovirology."

"Ultimately," said co-author Malik, "if we want to understand why our defenses are the way they are, the answers inevitably lie in these ancient viruses more so than the ones that have affected us only recently, such as HIV."

This work was supported by National Institutes of Health grants to Emerman, a Searle Scholar Award to Malik and a National Science Foundation graduate fellowship to Kaiser.