Methionine synthase, a promising drug target candidate, being evaluated in Manchester

Submitted by GAtherton on 10 December 2020

Manchester Fungal Infection Group

It is unbelievable that as of today there are only three classes of antifungal drugs in clinical use for deep infections: azoles, polyenes (amphotericin-B) and echinocandins (four, if we count flucytosine). These drugs have been paramount in the fight against fungal infections and have saved many, many lives. However, their use is becoming restricted due to the surge in resistant isolates. Therefore, it is clear that new antifungal drugs are urgently needed. There is hope, nevertheless, as various antifungal drugs are currently being evaluated in clinical trials. The scientific, physician and patient communities are excited about the revolution that these new treatments will have on the management of infections. We believe that this should become a trend and novel drugs, particularly with novel mechanisms of action, should be constantly under development.

In the Manchester Fungal Infection Group we have recently characterised a promising new target candidate for drug development: methionine synthase. This protein is known to be essential for various fungal pathogens (including Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans), which means that these fungi cannot live without it… at least in our petri dishes in the laboratory. However, if we aim to develop a new drug to target it, we need to be sure that inactivating methionine synthase will inhibit fungal growth inside a human body. In addition, it is important to understand the mechanism of action, as this may help to prepare for and mitigate the development of antifungal resistance against the new drug. These are the questions we have addressed in our recent study.

As it can be inferred from its name, methionine synthase forms methionine, one of the proteinogenic amino acids. It was expected that if we supplemented methionine to the fungi, we could be able to inactivate methionine synthase and they should be able to grow. But that was not the case, and is the reason why we call this protein “essential”. The question was, why is it essential? In our recent study we have taken quite a few different approaches to finally disclose that, when methionine synthase activity is blocked, there is a metabolic imbalance that causes a reduction in cell energetics. So, basically, the fungal cells cannot produce the energy they need and just stop growing. This is useful information that will help to decide the best treatment courses and combinations to prevent the development of resistance.

In addition, we have optimised a genetic system to mimic drug treatment in a living model of infection. Using this model, we have been able to show that targeting methionine synthase in an established infection confers a beneficial effect on the outcome. Therefore, we could conclude that targeting methionine synthase is a suitable strategy to treat aspergillosis infection.

In conclusion, we have validated methionine synthase as a promising target for the development of new antifungals. We will work now towards that aim.

Scott J, Sueiro-Olivares M, Thornton BP, Owens RA, Muhamadali H, Fortune-Grant R, Thomson D, Thomas R, Hollywood K, Doyle S, Goodacre R, Tabernero L, Bignell E, Amich J. 2020. Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth, and virulence. mBio 11:e01985-20.

Dr Jorge Amich | MRC Career Development Fellow

Manchester Fungal Infection Group (MFIG)

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