Cryogenic electron microscopy reveals drug targets against a common fungus

Most people carry the fungus Candida albicans on their bodies, without causing much trouble. However, a systemic infection with this fungus is dangerous and difficult to treat. Few antimicrobials are effective and drug resistance is increasing. An international group of scientists, including Albert Guskov, associate professor at the University of Groningen, used single-particle cryogenic electron microscopy to determine the structure of the fungal ribosome. Their results, which were published in Scientists progress on May 25, reveal a potential target for new drugs.

Candida albicans usually causes no problems or just an itchy skin infection that is easily treated. However, in rare cases, it can cause systemic infections that can be fatal. Existing antifungal drugs cause many side effects and are expensive. Otherwise, C. albicans is increasingly resistant to drugs, so there is a real need for new drug targets. “We noted that no antifungal drug targets protein synthesis, while half of the antibacterial drugs interfere with this system,” Guskov says. One reason for this is that fungal ribosomes, the cellular machinery that translates 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. »

Atomic resolution

Therefore, Guskov and his collaborators believed that obtaining the structure of the C. albicans ribosomes would be valuable for finding drug targets. The classic approach is to grow crystals from purified ribosomes and determine their structure using X-ray crystallography; however, it is a laborious technique. Instead, they used single-particle cryogenic electron microscopy, where large numbers of single particles are imaged at very low temperatures in an electron microscope. Images of individual particles – seen from different angles – are then combined to produce an atomic-resolution structure.

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Mutation

“In this way, we resolved the structures of the vacant and inhibitor-bound fungal ribosomes and compared their functions to those of yeast and rabbit ribosomes – the latter as a model for the human ribosome – and repeated this for the bound ribosomes. to different inhibitors,” says Guskov. One such inhibitor was the antimicrobial cycloheximide (CHX), to which C. albicans is known to be resistant. Comparing the structures, the scientists noted that a single mutation in the E site, which plays a key role in protein synthesis, prevents CHX from binding to C. albicans the ribosomes. “The mutation changed an amino acid in the structure of this E site from proline to glutamine. This substitution reduces the size of the binding site, so that the inhibitor cannot bind and is therefore ineffective. Another inhibitor, phyllanthoside, is not blocked by the mutation.

Menace

“By comparing the structures of E sites in vacant ribosomes in C. albicans and humans and information on how different inhibitors bind to the site, we can develop a specific inhibitor that blocks fungal ribosomes but not human ones. It would then be a selective drug to treat fungal infections. Scientists are currently examining libraries of molecules to find leads for drugs. “It is extremely difficult to develop a vaccine against C. albicans, as we did for the coronavirus. So we need drugs to treat systemic infections,” says Guskov. “The growing drug resistance of this fungus is a real threat. If this continues, we could be in serious trouble unless new drugs are developed.

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Materials provided by University of Groningen. Note: Content may be edited for style and length.

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