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Role of Hydrogen Sulfide in Iron Uptake and Antibiotic Resistance in E. coli
Antibiotic resistance poses a significant challenge in the treatment of bacterial infections, especially those caused by pathogenic organisms such as Escherichia coli. One of the biological processes that facilitate bacterial survival under stress conditions is the regulation of hydrogen sulfide (H2S), a potent chemical signaling molecule. Recent research has shed light on how H2S impacts not only oxidative stress responses but also plays a crucial role in iron uptake in these bacteria.
Iron is an essential nutrient for bacterial growth, but its availability can affect the ability of pathogens to survive antibiotic treatment. Previous studies in other pathogenic bacteria like Vibrio cholerae suggested that increased iron uptake could be linked to elevated levels of intracellular H2S, enhancing their response to oxidative stress. Nonetheless, the mechanisms by which H2S influences iron uptake in E. coli were still poorly understood.
To address this gap, a research team led by Professor Shinji Masuda at the Tokyo Institute of Technology investigated the interaction between intracellular H2S levels and iron uptake in E. coli. To study this phenomenon, they utilized a genetically modified strain of E. coli that overexpresses the mstA gene, which encodes the enzyme responsible for the synthesis of H2S.
The team employed advanced genetic analysis techniques, including RNA sequencing, to explore the molecular pathways linked to iron uptake in response to H2S. The results of their investigation were published in the mBio journal.
Professor Masuda elaborated on the research’s background, stating that their group had previously identified a transcription factor named SqrR in the purple photosynthetic bacterium Rhodobacter capsulatus, which regulates gene expression in response to H2S levels. He noted that YgaV, the homolog of SqrR in E. coli, has been associated with the repression of anaerobic respiratory genes in environments lacking extracellular sulfide. This prompted the team to delve deeper into the connection between intracellular H2S, YgaV-dependent transcription, and iron uptake.
Through their studies, the researchers found that the overexpression of mstA in the wild-type E. coli strain led to a significant increase in intracellular H2S levels, which was associated with enhanced antibiotic resistance. Further analysis revealed that several genes were upregulated in response to elevated H2S levels, including a 10-fold increase in the transcript levels of the tcyP gene, which encodes a transporter for L-cysteine, a sulfur-containing amino acid.
Moreover, the researchers noted a marked upregulation of the cysteinyl-tRNA synthase gene, which is involved in synthesizing supersulfides—molecules composed of self-linked sulfur atoms. These compounds have been implicated in the inactivation of β-lactam antibiotics, highlighting a potential mechanism for increased antibiotic resistance in E. coli under conditions of H2S overproduction.
The study also indicated changes in the expression of genes related to antibiotic efflux pumps and the downregulation of genes associated with dipeptide/heme transporters, suggesting a relationship between the accumulation of H2S and iron uptake pathways.
To dissect the role of YgaV further, the team employed a ΔygaV mutant strain of E. coli—where the ygaV gene is not expressed yet mstA is overexpressed. They discovered that the presence of YgaV was essential for the expression of several iron uptake genes, including fes, fepA, fhuE, fhuF, nfeF, and cirA, thereby confirming the dependency of these genes on intracellular H2S levels.
Professor Masuda concluded, “This study provides critical insights into iron uptake regulation in E. coli and underscores the significance of H2S-dependent YgaV in orchestrating the bacterial response to oxidative stress and enhancing antibiotic resistance.”
More information: Shouta Nonoyama et al, Increased intracellular H2S levels enhance iron uptake in Escherichia coli, mBio (2024). DOI: 10.1128/mbio.01991-24
Provided by: Tokyo Institute of Technology
Source
phys.org