How does the switch work?

The system Smith's team mapped operates like a sensitive switch with two components:

• BqsS, a protein embedded in the cell membrane, detects iron outside the cell and passes a signal inward.
• BqsR, a protein inside the cell, receives that signal, binds to DNA, and switches genes on or off across a wide range of cellular functions.

The paper confirms the pair regulates iron uptake into the cell. But it goes further. "What we didn't expect to find was how much the presence of this one ion rewires the bacterium, completely changing all sorts of genes," Smith said. "It's got hands in a lot of different pies."

The researchers also found a second layer. BqsR itself can bind iron inside the cell. When internal iron climbs too high, BqsR grabs the metal, releases the DNA it was attached to, and shuts off the corresponding genes.

"It's like a multilayered cake where there are all these different layers of sensing that are happening in this system," Smith explained.

In plain terms: one protein watches the outside, one watches the inside, and together they tune hundreds of genes to iron supply.

Who did the work?

Paredes made history at UMBC as the university's first graduate student named an HHMI Gilliam Fellow, an early-career program that funds Ph.D. students and their advisers pursuing ambitious science while building inclusive training environments. Undergraduates and other graduate students in Smith's lab contributed, along with collaborators at Oklahoma State University and Reed College.

"We couldn't do the work without them. Period, period, end of story," Smith said. "These types of publications are like an all-hands-on-deck kind of publication. Research experience prepares them to be more critical. It prepares them to solve problems."

What could this change for treatment?

The findings are preliminary, and no therapy yet exists. But the logic is concrete: because the BqsS/BqsR system controls both iron acquisition and biofilm formation, a drug that jams the switch could strip bacteria of two defenses at once—nutrient control and physical shielding. Related systems operate in other harmful bacteria, including the cholera pathogen, so the approach could extend beyond Pseudomonas.

Smith's team, working again with Oklahoma State colleagues, plans next to examine how the membrane protein and its intracellular partner interact, which amino acid building blocks matter most, and how the system responds to oxygen. Students will test these ideas in living bacteria, moving from basic mechanism toward strategies that could one day improve treatment of antibiotic-resistant infections.

"Hard work and luck both play into it," Smith said. "It's been such a collaborative effort that's gone into solving these harder problems that bridge biology, chemistry and everything in between."

Reference: Alexander Paredes et al., "The response regulator BqsR/CarR controls Fe²⁺ acquisition in Pseudomonas aeruginosa," Nature Communications (2026). DOI: 10.1038/s41467-026-76130-1.

One takeaway: a single iron ion, sensed from two directions, commands enough of this pathogen's biology to make its sensing machinery a serious drug target.