Many disease-causing bacteria — including pathogens that can cause cholera, meningitis, and certain types of pneumonia — contain an enzyme called Na⁺-NQR. The enzyme is essentially a pump that helps bacteria generate energy by moving sodium ions across their cell membranes while transferring electrons.  

Crucially, the enzyme is present in many types of harmful bacteria but not in the cells of humans and other animals, making it an ideal target for future antibiotics. But to disrupt the enzyme’s functions, scientists need to understand how, exactly, it works. An international team of researchers, including RPI postdoctoral fellow Moe Ishikawa-Fukuda, Ph.D., and Biological Sciences Professor Blanca Barquera, Ph.D., recently took a major stride in that direction with the publication of a new paper in Nature Communications. 

In the paper, Barquera and her colleagues used cryo-electron microscopy and computer simulations to capture “snapshots” of Na⁺-NQR in different stages of action. By studying mutant versions of the enzyme, adding specific chemical inhibitors, and removing sodium from the solution, they effectively "froze" its molecular machinery at various points in its operation. 

They found that the enzyme changes its physical configuration as it works, and identified at least five different structural configurations corresponding to different states in the bacterial energy cycle. 

“Na⁺-NQR has long been a bit of a puzzle for researchers, because certain parts of the enzyme appeared to be too far apart to facilitate the electron transfer that’s critical for bacterial respiration,” Barquera said. “With this work, we have documented how the enzyme reconfigures itself to make electron transfer possible.” 

This mechanism is fundamentally different from how cellular respiration works in humans and other animals, meaning that Na⁺-NQR is an ideal target for future antibiotics.  

“Knowing how the enzyme works is key to disrupting its action,” Barquera said. In future studies, the team will explore whether the structural states they identified can be targeted to effectively shut down the enzymatic pump.