Microbial diseases pose a major threat to humanity as COVID 19 demonstrates. Staphylococcus aureus resistance to this day remains at the origin of many infectious diseases. Invasive methicillin-resistant Staphylococcus aureus (MRSA) infections are still a killer with 120,000 bloodstream infections and 20,000 associated death in the United States alone in 2017.
Ribosome of S. aureus has been a solid antibiotic target for treating the infection, however with the constant evolution and development of bacterial resistance, novel discoveries of ribosomal mechanism are required to battle the bacteria.
The key to the survival of these bacterial cells lies in a mechanism of reduced energy consumption under adverse conditions. Joined forces of Cryo-EM and X-Ray crystallography allowed to demonstrate the mechanism of binding of RsfS protein to the uL14 protein of the large 50S ribosomal subunit. This fundamental research is a long way from a cure but it certainly helps pave the way to the design of drugs to combat this deadly pathogen.
a The 3.2 Å cryo-EM density map. Ribosomal protein uL14 is colored in dark blue, bL19 in bright blue, 23S rRNA Helix 95 in white, and RsfS in orange. CP central protuberance. b A low-pass filtered map of the 50S–RsfS complex (Gaussian filter with the width equal to 3.5 voxel size of the initial map) was used for the initial flexible fitting of the molecular model. c, d Density corresponding to the RsfS beta-sheet assembly and model is fitting. For representation reasons, a Gaussian filter with the width equal to one voxel size (outer mesh) was applied to the initial cryo-EM map (inner mesh). e The uL14–RsfS interaction interface as seen in the cryo-EM map (a Gaussian filter with the width equal to 1.5 voxel size applied). f Electrostatic potential of uL14 and RsfS (surface representation) calculated from the model; the structural elements involved in contacts formation are shown as ribbons and labeled. g The RsfS-binding cavity, including uL14, bL19, and H95. Molecules are shown in surface representation. Close-up sections demonstrate potential interacting residues of the proteins (represented as sticks).
Collaborators; Kazan Federal University of Russia, the Institute of Genetics and Molecular and Cellular Biology (IGMBC, France), the Institute of Protein Research of the Russian Academy of Sciences, the Institute of Microbiology (University of Stuttgart, Germany) and NovAliX (Strasbourg, France).
The results has been published in Nature Communications: https://www.nature.com/articles/s41467-020-15517-0