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Heme binding to a bacterial transcription factor is critical for hydrogen sulfide (H₂S) signaling, report researchers from Japan. Heme binding promotes the reaction of H₂S with the transcription factor, leading to structural changes that can regulate stress tolerance in bacteria.

The mechanism reported in this study explains bacterial resistance via H₂S sensing and highlights a previously unknown role of heme in cell signaling. Disrupting this mechanism could inspire new antibiotic strategies against drug-resistant infections.

Bacteria are remarkable microorganisms that can detect and respond to environmental signals via changes in their metabolism, gene expression, or physiology. Hydrogen sulfide (H₂S) –a small, naturally occurring gas with a single sulfur atom, is one such signaling molecule that plays a vital role in bacterial survival and stress tolerance.

In many bacterial species, exposure to H₂S triggers changes in genetic activity, which influences their response to oxidative stress and resistance against antibiotics. However, despite its importance, the ways in which bacteria sense and utilize H₂S remain unclear.

In this context, a team of researchers led by Professor Shinji Masuda, along with second-year Master's student Ryoma Iwata, from the Department of Life Science & Technology, Institute of Science Tokyo, Japan, conducted a study to uncover the precise molecular mechanisms through which H₂S signaling regulates genetic activity in bacteria.

The findings, published in , provide key insights into cell signaling in bacteria.

Using a combination of biochemical experiments and structural and functional studies, the researchers conducted a detailed analysis of transcription factors (DNA-binding proteins that regulate gene expression) in response to H₂S. The transcription factors—specifically, SqrR present in Rhodobacter capsulatus and YgaV in Escherichia coli—were analyzed under both the presence and absence of heme (an iron-containing molecule) and oxygen.

The team discovered that when H₂S enters the bacterial cell, the heme bound to the transcription factor catalyzes a reaction that converts H₂S into a different sulfur-containing molecule called polysulfide. Polysulfides are characterized by the presence of intramolecular S–S bonds and are highly reactive towards proteins.

Therefore, when H₂S is converted to a polysulfide, it readily reacts with the transcription factor in the presence of oxygen, forming a tetra-sulfide (S–S–S–S) bridge between the protein's cysteine residues. This subtle modification is critical for the transcription factor's gene-specific activity.

"Heme not only detects H₂S but also drives a chemical change in the protein that directly impacts gene control," says Masuda, "which highlights the critical role of heme in bacterial survival."

Once modified, the transcription factors lose their ability to bind to specific DNA molecules, which causes increased expression of genes involved in sulfide metabolism, anaerobic respiration, and oxidative stress tolerance. This, in turn, leads to antibiotic resistance and helps in bacterial survival.

There is, however, a catch—in the absence of oxygen, heme binding blocks the oxidation reaction and prevents polysulfides from modifying the transcription factors, suppressing sulfides signals in oxygen-deficient conditions.

Overall, these findings mark a milestone in molecular science, reshaping our understanding of heme's role in biology. While heme is mostly known for carrying oxygen in hemoglobin and participating in cellular energy production, this study uncovers how it can also serve as a catalyst for precise chemical modifications that regulate gene expression.

Highlighting the significance of this study, Masuda says, "Since this mechanism is very different from other well-known bacterial defenses, targeting it could lead to novel antibiotics and offer a new angle for undermining antibiotic resistance."

In the future, the researchers plan to explore whether similar heme-based sensing systems operate in other bacteria or respond to other signaling molecules.

Understanding these pathways could uncover entirely new strategies to combat antibiotic resistance—one of the most pressing challenges in modern medicine.