Diamond lights path to new antibiotic targets according to researchers
Bacteria react to stressful conditions like a lack of nutrients, host immune systems or anti-infectives in a variety of ways. The responses - which can include producing a resistant outer coat or synthesising defensive enzymes - are mediated by the expression of otherwise dormant defensive genes.
The expression of these genes is triggered by sigma54 according to researchers from the UK, China and the US who say their detailed study of the protein – reported in Science this week – could be used to develop new ways of treating bacterial infection.
Researcher Xiaodong Zhang told us “under stressful conditions, sigma54 interacts with an activator protein causing rearrangements of sigma54 structure, to allow RNA polymerase to start gene transcription and trigger the defence system.”
He explained that sigma54 targets a variety of regions within RNA polymerase to stop it from working, adding that these regions – along with the protein itself – could be examined as targets for new therapies.
“We can look into developing antibiotics that target these regions within RNA polymerase, hence kill the bacteria. sigma54 itself, or its specific interaction with RNA polymerase, can also be a target so that the bacterium's defence system will be weakened.”
Zhang added that: “Currently we are focusing on the fundamental mechanisms but our next step will be to develop drugs, either with pharmaceutical companies or within academic environment.”
Synchrotron
sigma54’s involvement in bacterial defence mechanisms was already established. However, its precise role and function had not been previously determined.
Key to the discovery was the UK’s Diamond Light Source – which is a giant electron accelerator near Oxford that produces extremely bright light that can be used to study everything from protein molecular structure to material surfaces.
Zhang and his team use the technology – known as a synchrotron – to study sigma54’s structure and determine how it interacts with the enzyme responsible for triggering bacterial stress responses.
Source: Science
“Structures of the RNA polymerase-s54 reveal new and conserved regulatory strategies”
Authors: Yun Yang, Vidya C. Darbari, Nan Zhang, Duo Lu, Robert Glyde, Yiping Wang, Jared Winkelman, Richard L. Gourse, Katsuhiko S. Murakami, Martin Buck, Xiaodong Zhang.
DOI: 10.1126/science.aab1478
