Cornell researchers have discovered a pathway by which E. coli regulates all-important zinc levels, an insight that could advance the understanding of metal regulation in bacteria generally and lead to antibacterial applications such as in medical instruments and surgical settings.
Peng Chen, the Peter J. W. Debye Professor of chemistry and chemical biology in the College of Arts and Sciences (A&S), is corresponding author of “A ‘Through-DNA’ Mechanism for Co-regulation of Metal Uptake and Efflux,” which published Dec. 4 in Nature Communications.
Co-first authors are postdoctoral researcher Udit Kumar Chakraborty, Ph.D. ’24, and research associate Youngchan Park.
Living cells need zinc – among other metals – to function properly, and maintaining balanced levels is critical to cell health. E. coli have evolved mechanisms to bring in more zinc when it’s needed and to get rid of extra to avoid toxicity, Chen said; his lab has discovered a previously unknown pathway the bacteria can use to control cellular zinc levels.
The researchers found that the metal-regulating proteins Zur and ZntR – which control uptake and efflux (outflow), respectively – can cross-interact directly through the cell’s DNA, providing another way for the two metalloregulators to coordinate their actions as they control metal concentration in the cell. The more options the cells have, the faster they can balance critical zinc levels, saving the life of the cell.
Scientists have long understood that each of these metalloregulator proteins acts on DNA to control the transcription calling for zinc uptake or efflux. In this process, the metalloregulator must bind physically to the DNA and then unbind from the DNA.
Studying E. coli DNA, the researchers found that the DNA sequences Zur and ZntR recognize overlap partially, raising the question of whether they really can cross-interact. The experiment proving that they can was the first in-cell study of protein-DNA interaction kinetics as a function of concentration of two proteins.
The additional pathway allows Zur to unbind faster from DNA in the presence of ZntR, speeding the balance of metal levels.
“Let’s say you want to change the cellular state to getting more zinc in – you want to switch to that state quickly, so you don’t have to wait,” Chen said.
The researchers expect that other bacteria also use this pathway. The mechanism may also be present in yeast, a higher organism. They are working to confirm this, as well as looking at other metalloregulators that deal with other transitional metals, such as nickel and iron.
Silver and copper are already used in medical instruments and facilities to prevent bacterial infections, Chen said, and this new insight into additional metal control mechanisms could add ways of killing bacteria when it counts.
“How bacteria handle the concentration of metals are essential for them to survive,” he said, “so any mechanisms we can identify that can be disrupted could have an antibacterial effect.”
The research received support from the ³Ô¹ÏÍøÕ¾ Institutes of Health.
Kate Blackwood is a writer for the College of Arts and Sciences.
