Bacterial structures are critical to the development of new antibiotics

By Samantha Black, PhD, The Science Advisory Board editor in chief

A research team from Cornell University have uncovered a unique regulatory mechanism unique to bacterial that may provide crucial insight for antibiotic targeting of pathogens. The work was published in Nature Structural & Molecular Biology on November 18.

Understanding underlying cellular mechanisms in pathogens is becoming increasingly important as the concern over antibiotic-resistant bacteria grows. This will allow researchers to identify new therapeutic targets based on new discoveries.

The T-box is a relatively large DNA binding domain which contains transcription factors that govern the bacterial response to amino acid starvation by triggering a series of events to increase the production of proteins in the cell. The T-box region recognizes many transcription factors for protein synthesis. In this way, T-boxes are essential for properly functioning cells, including pathogens such as Mycobacterium tuberculosis.

"The T-boxes are only found in bacteria and they control essential genes," said study first author Robert Battaglia. "This makes them an attractive target because they are also essential for a lot of these bacteria to respond to starvation conditions."

T-boxes contain five structural domains, Stem-I, Stem-II, Stem-IIA/B, Stem-III and antiterminator (AntiT) or antisequestrator (AntiS). This structure uniquely binds uncharged transfer RNA (tRNA) for upregulation of protein synthesis. Previous research shows that once the T-box binds to the tRNA it is able to sense its aminoacylation state to begin the negative feedback loop. However, the mechanism for aminoacylation sensing and the roles of several t-box domains remain unclear.

In this study, the researchers use x-ray crystallography to present the crystal structures of the T-box riboregulatory from Mycobacterium tuberculosis. This allowed them to determine the structural basis of tRNA decoding and aminoacylation sensing (process by which tRNA is charged). They found that both the AntiT, Stem-III and adjacent linker region are required for aminoacylation sensing resulting in upregulation of amino acid production. They show that the ribosome is not the only structure capable of this process.

"By solving our structure, we're able to see how different parts of the T-box are positioned to allow the T-box to have this specific interaction with a tRNA," Battaglia said. "If we can develop some sort of drug to target these T-box elements to mess with their ability to bind with the tRNA, they could be a really good choice for an antibiotic because we don't have [T-boxes] ourselves, so we don't have to worry about side effects or toxicity."

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