Scientists have shown how a bacterial protein senses changes in temperature to slacken DNA strands and boost gene expression in some foodborne pathogens.
The approach may open new avenues to control pathogenic multi-drug resistant bacteria, according to researchers from the King Abdullah University of Science and Technology (KAUST) in Saudi Arabia.
Pathogenic bacteria come alive when they enter the warm human gut, starting up genes that encode toxins and other harmful compounds.
Temperature prompts protein action
The histone-like nucleoid-structuring (H-NS) protein is crucial for adaptation and toxicity control of human pathogens such as Salmonella, Vibrio cholerae or enterohemorrhagic E. coli.
These gut-dwelling bacteria that cause foodborne illness use this protein to condense their DNA and restrict gene expression. H-NS has a way of helping the microbes stay mostly dormant when free-floating in the environment. However, the protein must release its grip on DNA to allow the bacteria to thrive in a warm-blooded host, according to the study published in Nucleic Acids Research.
Current consensus is an increase in temperature from ambient to the 37 degrees C (98.6 F) inside an animal host disrupts the self-association of H-NS, which weakens its grip on DNA, and its capacity to compact DNA and repress gene expression. However, the molecular mechanism through which H-NS senses temperature and other physiochemical parameters was unclear.
“Having determined how these bacteria sense that they are inside humans, we could try to conceive of small molecules to perturb this mechanism. Such compounds would block bacteria from adapting to their environment, which would weaken them and facilitate eliminating them,” said research scientist Umar Hameed.
Preventing bacteria expressing toxins
Combining structural, biophysical and computational analyses, the team showed that human body temperature promotes unfolding of the central dimerization domain, breaking up H-NS multimers.
They identified the part of H-NS, called site2, that changes in response to a temperature rise, prompting the protein complexes to fall apart. Researchers demonstrated partial disassembly of the H-NS complexes leads the protein to adopt a self-inhibiting form that also blocks its ability to bind and recognize DNA.
Data provided evidence against a model where temperature, salt or acidity are sensed through a parallel-to-antiparallel structural transition of site1.
The team now hope to develop drugs that can stabilize the connection between proteins at human body temperature and prevent H-NS complexes from fragmenting.
Computer simulations were performed with KAUST colleague Xin Gao and Jianing Li at the University of Vermont.
“If we can find compounds that reinforce the structure against heat-induced unfolding then bacteria would not express toxins anymore; they would remain inoffensive and be generally weakened inside humans,” said group leader, Stefan Arold.
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