Antibiotic resistance is said to become a global burden on healthcare systems, as well as a more immediate threat to public health. A bacterial protein called MraY is a promising target for new antibiotics, but the protein’s structure has remained a mystery.
Now, researchers at Duke University have crystallized MraY and further characterized it. The findings could lead to the development of a more effective antibiotic that could be used against serious bacterial infections like tuberculosis and MRSA.
The study led by Seok-Yong Lee and his lab at Duke was published in the journal Nature this week.
The team gained insights into the structure and folding of this key bacterial protein using a technique called X-ray crystallography, giving the researchers a chance to observe the three-dimensional image of the protein.
They discovered that when the naturally occurring inhibitor muraymycin D2 binds to MraY, a dramatic change occurs and two new binding sites open up. The researchers suspect the so-called “conformational plasticity” of MraY could explain why there are many structurally distinct inhibitors that target MraY.
"Nature has evolved a number of ways to inhibit this enzyme, but researchers haven't been able to mimic their properties in the laboratory," said Lee in a statement. "Here, we provide a platform for understanding how these natural inhibitors work, with the degree of molecular detail necessary to accelerate drug development."
MraY is a prime antibiotic target since it’s a protein found in the cell wall of all bacteria. Without a cell wall, a single bacterium is vulnerable to outside invaders and therefore cannot survive and reproduce.
Since 5 different naturally occurring antibiotics that target MraY have been discovered so far, it demonstrates the number of potential targets for disabling this protein.
"Many natural product inhibitors bind and inhibit this enzyme in a different way, by a different mechanism," Lee said. "If we understand every possible mechanism of inhibition of this enzyme, then we may be able to translate that knowledge into the development of drugs that can target it with the most specificity."
Their next step is to visualize MraY bound to other natural inhibitors, characterizing the binding affinity and potency of these potential antibiotic drugs.