Most people carry the fungus Candida albicans on their bodies, without causing many problems. However, when a systemic infection occurs with this fungus, it is dangerous and difficult to treat. The fungus is also becoming more drug resistant, so there is a need for new drug targets. Now, an international group of scientists, including Albert Guskov, PhD, associate professor at the University of Groningen, have used single-particle cryogenic electron microscopy to determine the structure of the fungal ribosome. Their findings reveal a potential therapeutic target.

Their findings were published in the journal Science Advances in a paper titled, “E-site drug specificity of the human pathogen Candida albicans ribosome.”

Candida albicans is a widespread commensal fungus with substantial pathogenic potential and steadily increasing resistance to current antifungal drugs,” wrote the researchers. “It is known to be resistant to cycloheximide (CHX) that binds to the E–transfer RNA binding site of the ribosome. Because of the lack of structural information, it is neither possible to understand the nature of the resistance nor to develop novel inhibitors. To overcome this issue, we determined the structure of the vacant C. albicans 80S ribosome at 2.3 angstroms and its complexes with bound inhibitors at resolutions better than 2.9 angstroms using cryo–electron microscopy.”

We noted that no antifungal drugs are targeting protein synthesis, while half of the antibacterial drugs interfere with this system,” explained Guskov. “A reason for this is that fungal ribosomes, the cellular machineries that translate the genetic code into proteins, are very similar in humans and fungi. So, you would need a very selective drug to avoid killing our own cells.”

The researchers used single-particle cryogenic electron microscopy.

“In this way, we solved the structures of vacant and inhibitor-bound fungal ribosomes and compared their functions to those of ribosomes from yeast and rabbit—the latter as a model for the human ribosome—and repeated this for ribosomes bound to different inhibitors,” said Guskov.

By comparing the structures, the scientists noted that a single mutation in the E-site, which plays a key part in protein synthesis, prevents CHX from binding to C. albicans ribosomes. “The mutation changed one amino acid in the structure of this E-site from proline to glutamine. This substitution reduces the size of the binding site, so the inhibitor can’t attach and is therefore ineffective.”

Guskov noted, “By comparing the structures of the E-sites in vacant ribosomes in C. albicans and humans and information on the way that different inhibitors bind to the site, we can develop a specific inhibitor that blocks fungal ribosomes but not those of humans. This would then be a selective drug to treat fungal infections.”

The researchers are currently screening libraries of molecules to find drug leads. “It is extremely challenging to develop a vaccine against C. albicans, like we did for the coronavirus. So, we need drugs to treat systemic infections,” Guskov explained. “The increasing drug resistance of this fungus is a real threat. If this continues, we could be in serious trouble unless new drugs are developed.”