Pseudomonas aeruginosa is a common culprit in hospital-acquired bacterial infections and is growing more resistant to antibiotics. New findings from Aaron Smith , professor of chemistry and biochemistry at UMBC, and collaborators at Oklahoma State University show how a two-protein system inside the bacterium operates like a sensitive switch: the pair detects iron both outside and inside the cell and then rewrites large parts of the microbe's metabolism in response. The results, published in Nature Communications , suggest this system could become a target for more effective treatments for stubborn infections.
Like most living things, Pseudomonas requires iron to survive. Bacteria prefer reduced, ferrous iron—a form with beneficial properties that is also sensitive to oxygen. That means ferrous iron is plentiful in low-oxygen microenvironments such as dental plaque, the lining of the gut, coatings on the lungs of people with cystic fibrosis, or the site of burn wounds. Bacteria can also generate these protective coatings, called biofilms, which help shield them from drugs and the immune system and contribute to antibiotic resistance.
Given iron's necessity, one way organisms fight invading microbes is by depriving them of it. As a result, bacteria have evolved complex mechanisms to monitor how much iron is available and in what form. The signaling system in Smith's current study is one such mechanism. One protein, called BqsS, sits in the cell membrane and senses iron outside. It then passes a signal to a second protein, called BqsR, inside the cell. Based on that signal, BqsR binds to DNA and turns genes on or off, affecting a wide range of cellular functions.
A "multi-layered cake" of sensing
The new paper shows that BqsR and its partner regulate iron uptake into the cell, but also that the system does far more. "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 says. "It's got hands in a lot of different pies."
The researchers were also surprised to learn that BqsR itself can bind iron inside the cell. When iron levels rise too high, BqsR binds the iron and lets go of the DNA it had been attached to, turning off the corresponding genes. "It's like a multi-layered cake where there are all these different layers of sensing that are happening in this system," Smith explains.
Student-driven discovery
The work was led by first author Alexander Paredes, Ph.D. '25, the first UMBC graduate student named an HHMI Gilliam Fellow , an early career initiative that supports Ph.D. students and their faculty advisors as they pursue ambitious science and build inclusive training environments. Today Paredes is a postdoctoral researcher in chemist Squire Booker 's lab at the University of Pennsylvania.
The project also involved undergraduates and other graduate students in Smith's lab, along with collaborators at Oklahoma State University and Reed College.
"We couldn't do the work without them. Period, period, end of story," Smith says. "These types of publications are like all-hands-on-deck kind of publications. Research experience prepares them to be more critical. It prepares them to solve problems."
Treatments of tomorrow
The discoveries point toward possible new ways to fight infection. Because the same system that manages iron also controls biofilm formation, disrupting it might force bacteria out of their protective coatings and make them more vulnerable to existing antibiotics. Related systems exist in other harmful bacteria, including the one that causes cholera, so this line of research could be broadly applicable.
A new NIH grant will let Smith's team dig deeper into the molecular details of this iron-management system, again in collaboration with colleagues at Oklahoma State. The interdisciplinary team will examine how the membrane protein and its counterpart inside the cell interact, which building blocks of each protein are most critical, and how the system responds to oxygen. Students in the lab will help test these ideas in living bacteria, aiming to move from basic understanding toward strategies that could one day improve treatment of antibiotic-resistant infections.
"Hard work and luck both play into it," Smith says. "It's been such a collaborative effort that's gone into solving these harder problems that bridge biology, chemistry, and everything in between."
