Cryogenic electron microscopy finds drug targets against common fungus

Most people carry the fungus Candida albicans on their bodies, without causing many problems. 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, has used single-particle cryogenic electron microscopy to determine the structure of the fungal ribosome. Their results, published May 25 in Science Advances, reveal a potential target for new drugs.

Candida albicans usually causes no problems or just an itchy skin infection that is easy to treat. However, in rare cases, it can cause systemic infections that can be fatal. Existing antifungals cause many side effects and are expensive. In addition, C. albicans is becoming increasingly drug resistant, so there is a real need for new drug targets. “We noticed that no antifungal drugs target 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 translate the genetic code into proteins, are very similar to humans and fungi. “So you would need a very selective drug to avoid killing our own cells.”

Atomic Resolution

Therefore, Guskov and his collaborators reasoned that obtaining the structure of the ribosomes of C. albicans would be valuable in finding drug targets. The classical approach is to grow crystals from purified ribosomes and determine their structure using X-ray crystallography; however, this is a cumbersome technique. Instead, they used single-particle cryogenic electron microscopy, which involves imaging a large number of individual particles at very low temperatures in an electron microscope. The images of individual particles — viewed from different angles — are then combined to produce an atomic resolution structure.

Mutation

“In this way, we solved the structures of empty and inhibitor-bound fungal ribosomes and compared their functions with those of yeast and rabbit ribosomes – the latter as a model for the human ribosome – and repeated this for ribosomes bound to different inhibitors,” explains Guskov out. One of these inhibitors 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 ribosomes. ‘The mutation changed one amino acid in the structure of this E-site from proline to glutamine. This substitution reduces the binding site, which prevents the inhibitor from attaching and is therefore ineffective.’ Another inhibitor, phyllanthoside, is not blocked by the mutation.

Threat

‘By comparing the structures of the E sites in empty ribosomes in C. albicans and humans and information about how different inhibitors bind to the site, we can develop a specific inhibitor that blocks fungal ribosomes, but not those in humans. This would then be a selective drug to treat fungal infections.’ The scientists are currently screening libraries of molecules to find drug leads. “It is quite a challenge to develop a vaccine against C. albicans, as we did for the coronavirus. So we need drugs to treat systemic infections,” explains Guskov. ‘The increasing drug resistance of this fungus is a real threat. If this continues, we could be in serious trouble if new drugs are not developed.”

Reference: Yury Zgadzay, Olga Kolosova, Artem Stetsenko, Cheng Wu, David Bruchlen, Konstantin Usachev, Shamil Validov, Lasse Jenner, Andrey Rogachev, Gulnara Yusupova, Matthew S. Sachs, Albert Guskov and Marat Yusupov: E-site drug specificity of the human pathogen Candida albicans ribosome. Science Progress, May 25, 2022

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