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Scientists have long been fascinated by two promising classes of antibiotics that disable RNA polymerase (RNAP). They knew that these drugs could grind gene expression to a halt in several pathogens, including the bacterium behind tuberculosis, by binding to specific locations in the RNAP. But despite decades of study, a key question remained: what process are the drugs actually targeting?

Now, a new paper in PNAS solves that mystery and simultaneously uncovers a new element of basic biology. Using these antibiotics as tools to clarify the finer points of RNAP function, the researchers discovered that the enzyme works only if a certain moving part briefly swings into place to stabilize RNA synthesis—and that these drugs disable the enzyme by preventing that motion. The findings reveal a previously unknown mechanism of RNA synthesis shared across diverse forms of life and lay the groundwork for developing next-generation antibiotics.

“It’s sort of a two-for-one,” says the senior author. “We now know how these inhibitors work, and the inhibitors also revealed a conformational change in the active site that we didn’t know was important.”

This perspective provides an overview of the growing literature on the role of the immune system in driving neurodegeneration and argues that restoring neuroimmune dialogue, rather than simply clearing protein aggregates, is the next frontier for therapeutic development.