International research finds new vulnerabilities in Candida albicans

June 8th, 2022

Q56 prevents binding of CHX to the C. albicans ribosome. (A) Overview of the CHX binding site (red) in the C. albicans 80S ribosome. The 40S subunit is shown in yellow, the 60S subunit is shown in blue, and mRNA and tRNA are shown in gray. The CHX molecule was superimposed from S. cerevisiae ribosome (PDB 4U3U), and mRNA and tRNAs were superimposed from the Thermus thermophilus (PDB 4V4Y). (B and C) Binding of CHX to the S. cerevisiae ribosome shown in two orientations (PDB 4U3U) (9). (D and E) Close-up views of the C. albicans CHX binding site in two orientations. The glutarimide group of CHX clashes with the side chain of Q56 preventing CHX from binding to the ribosome of C. albicans. (F) Inhibition of translation by CHX in cell-free translation extracts (CFTSs) from C. albicans, S. cerevisiae, and rabbit reticulocytes. Cell-free experiments were performed twice using independent technical triplicates; the results of one set of triplicates are shown. The root mean square deviation of luciferase (LUC) activity was 2 to 5%. Credit: Kazan Federal University

A paper by Russian, French, American and Netherlandish scholars appeared in Science Advances.

The work was a part of Russian Science Foundation's grant project 'Structural basics of protein-synthesizing apparatus of Candida albicans'. Russia is represented by Kazan Federal University, Kazan Center of the Russian Academy of Sciences, and Moscow Institute of Physics and Technology.

Using cryoelectronic microscopy, the scientists were the first to determine the structure of the C. albicans ribosome with a high resolution (2.3 Å), as well as the structures of ribosome complexes with known antibiotics: cycloheximide, phyllantoside, anisomycin, and blasticidin S.

"Candida albicans is the most common pathogenic fungus, the causative agent of many superficial (affecting the skin or mucous membranes) and internal (candidiasis) infections. Its resistance to modern antifungal drugs is constantly increasing. Treatment of candidiasis requires the use of expensive drugs and in most cases does not guarantee complete cure. This is due to the ability of yeast-like fungi to develop resistance to modern drugs," comments Shamil Validov, Senior Research Associate of KFU's Structural Biology Lab.

According to the him, as a result of therapy, serious side effects often occur due to the fact that the cellular targets of yeast and humans are very similar.

Validov adds, "The action of more than 40 percent of antibiotics is aimed at blocking the work of the ribosome, the biological molecular machine responsible for protein synthesis in the cell. In higher organisms (including humans and fungi), ribosomes are largely similar, so the action of antibiotics can affect not only the metabolism of the pathogen, but also human cells. The result is side effects."

Another co-author, Lead Research Associate of the same laboratory Konstantin Usachev, explains, "We have found structure-specific regions of the E-site of the Candida albicans ribosome compared to the human ribosome, which opens up the possibility of developing a new selective inhibitor that blocks the functioning of the Candida ribosome. In addition, we managed to explain the reason for the resistance of Candida albicans to the antibiotic cycloheximide."

He noted that the data obtained will make it possible to develop new highly selective antifungal drugs that act on ribosome sites characteristic of Candida albicans.

More information:
E-site drug specificity of the human pathogen Candida albicans ribosome

www.science.org/doi/10.1126/sciadv.abn1062

Provided by Kazan Federal University