High resolution molecular structures produced by researchers at the University of Illinois Chicago show that the effectiveness of the macrolides class of antibiotics – and bacterial resistance to it – depends on interaction with a single water molecule.
Macrolides have a broad spectrum of use against most gram-positive bacteria and are a widely used treatment for a variety of infections. Clarithromycin, for example, is used as a mainstay treatment for respiratory infections. Due to antibiotic overuse, antibiotic resistance has emerged Macrolides interrupt protein biosynthesis in the ribosomes of pathogenic bacteria, and are one of the most successful classes of antibiotics to use this mechanism of action. The macrolides accomplish this by entering the cell and binding to the bacteria’s ribosomes, preventing them from manufacturing and releasing new proteins. As a result of the halt in protein synthesis, the bacteria can no longer grow or replicate. However, mutations came about that rendered the bacteria resistant.
Seeking to understand how the bacteria came about their resistance, the researchers learned how to capture images of the ribosome and the macrolide invading it. The researchers discovered that precisely one water molecule was required for the antibiotic to bind to the ribosome.
Corresponding author Yury Polikanov, associate professor of biological sciences at UIC, said: “We compared the hi-res structures of the ribosomes from sensitive and resistant bacteria and noticed that a water molecule that is needed for the tight antibiotic binding was not present in the ribosomes from the drug-resistant bugs. In the ribosomes from the drug-resistant bacteria, there was simply no room for this water molecule.”
The mutation that conferred macrolide resistance adds a pair of methyl groups to where the macrolide molecule normally binds to the ribosome, and the water molecule instead disrupts the binding.
“We are very much excited by this discovery,” Polikanov said. “Because we now know how exactly macrolide antibiotics interact with their target, the ribosome. This discovery is important because it will inform and facilitate the development of new antibiotics that do not need this water molecule for binding. There is a huge demand for such drugs that are able to kill even those bacteria that became resistant to the currently used drugs.”
Source: News-Medical.Net
Journal information: Svetlov, M.S., Syroegin, E.A., Aleksandrova, E.V. et al. Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance. Nat Chem Biol (2021). https://doi.org/10.1038/s41589-020-00715-0
