New research from Cornell University offers a new pathway for targeting pathogens in the fight against antibiotic-resistant bacteria.

As antibiotic resistance rises, the search for new antibiotic strategies has become imperative. Researchers used the Cornell High Energy Synchotron Source (CHESS) to reveal an unexpected mechanism of activation and inactivation in the protein ribonucleotide reductase (RNR). The findings were published in “Convergent Allostery in Ribonucleotide Reductase” in Nature Communications.

Understanding the “switch” that can turn RNR off provides a possible means to shut off the reproduction of harmful bacteria. RNRs take ribonucleotides, the building blocks of RNA, and convert them to deoxyribonucleotides, the building blocks of DNA. In all organisms, the regulation of RNRs involves complex mechanisms. Without these mechanisms, DNA replication becomes error prone, and dangerous mutations could occur.

“Without the RNR enzyme, DNA-based life as we know it could not exist,” said first author William Thomas, a graduate student in chemistry and chemical biology. “If we understand the RNR ‘off switch’ well enough, we can take advantage of it by developing our own ways to toggle it with new antibiotic drug molecules.”

This research reveals evolution in action, according to Nozomi Ando, assistant professor of chemistry and the paper’s senior author. The lack of the normal regulatory “switch” mechanism may provide an evolutionary advantage for the bacteria they studied.

“Usually the increased chance of mutations is a problem for bacteria, but maybe under certain circumstances it’s actually advantageous for an organism to mutate and possibly become resistant to an antibiotic or another stressful situation,” she said.

RNRs are not easy proteins to work with or understand, and the researchers said characterizing them in the traditional way has been challenging. “The combination of small-angle x-ray scattering using CHESS, crystallography, and cryo-electron microscopy is what made this study possible,” Ando said.

Co-authors include Cornell doctoral student Audrey Burnim; research associate John-Paul Bacik; F. Phil Brooks III of Princeton University; JoAnne Stubbe of the Massachusetts Institute of Technology; Jason T. Kaelber of Rutgers University; and James Z. Chen of Oregon Health and Science University.

The research was supported by the National Science Foundation and the National Institute of Health.