In 2014 the World Health Organization (WHO) issued a statement in which it declared, “A post-antibiotic era, in which common infections and minor injuries can kill, far from being an apocalyptic fantasy, is instead a very real possibility for the 21st Century.” This pending doom is evident as there was a new strain of ‘super gonorrhea’ reported in late 2015 in the UK, which defied the norms of pharmacological treatment. The standard of care for gonorrhea is a dual therapy using the antibiotic combination of ceftriaxone and azithromycin, but the cases reported in the north of England were resistant to azithromycin, rendering current therapies ineffective in treating the infection. This is only one example of resistance in recent history and in the UK was the topic of much discussion. But as we know only too well, infections that up until recently could be treated fairly reliably with a first-line therapy often require multiple cracks of the whip with second or third line treatment in order to achieve a recovery.

Pharma companies are being actively encouraged to invest in new ways to develop antibiotics. Indeed it has been discussed on many occasions, the activity of sourcing these new drug candidates is sending many head scratching researchers to consider animals, vegetables and minerals as the ground breaking source of something new to blast the super-bugs.

Scientists at Bristol University in the UK have turned to the common woodland mushroom in their hunt for success and their work seems to have resulted in what is being considered as a major breakthrough in new antibiotic therapy.

The research group, which is led by Professor Gary Foster and supported by GSK, has undertaken work with the mushroom Clitopilus passeckerianus, isolating derivatives, which are looking very promising in the search for the Holy-antibiotic-Grail. The outcomes of the Bristol-based group have resulted in the isolation of derivatives of the antibiotic pleuromutilin from the fungus. Pleuromutilins are one of very few new groups of antibiotics that have been discovered over recent years and are showing lots of promise especially in certain groups of infections such as methicillin-resistance Staphylococcus aureus (MRSA) and extensively drug resistant tuberculosis (XTB), both of which are potentially killer infections, especially in the elderly and immune-compromised patient populations.

The only problem is that the feathery little mushroom is a basidiomycete fungi, and its metabolic properties render it resistant to strain improvements and fermentation techniques, which are required to modify it in order to be able to progress with drug development. In order to try and work around this, a collaboration with GSK was undertaken in the form of a gene identification program that has facilitated research in order to identify the genes that are involved in the production of the pleuromutulins from the C. passeckerianus fungi.

The gene-based research has resulted in the identification of a seven-gene cluster, which is responsible for creating pleuromutulin in the specific mushroom. The isolation of this gene cluster in itself is a groundbreaking step. However, the team of scientists has taken it one step further and has had success genetically modifying a different mushroom in order to enable it to produce pleuromutilin. The Aspergillus oryzae belongs to a completely separate group of mushrooms, ascomycetes. Using a reconstructed gene structure the more robust specimen has been genetically modified in order to enable it to produce pleuromutilin at a vastly improved rate—more than 200 times faster (2106%) than the basidomycete.

The impact of the research, which was published in Nature (May 2016), is two-fold, aside from the fact that an increase in production rate of such an extent means there’s a greater quantity of the antibiotic made. What is probably more impactful is the successful transposition of a chemical production mechanism into an environment where previously no synthesis was possible.

Mushrooms are a great source of interest in antibiotic development and over the past years many different specimens have been cast aside, even with interesting molecules associated with them, simply because of lack of ability to develop and modify derivatives. The success of the Bristol group in being able create the genetic expression of a basidiomycete in an ascomycete could open up a whole new opportunity of researching previously overlooked fungi.

There is currently one semisynthetic pleuromutilin, retapamulin available on the market and the potential to now expand and employ the reported gene expression technique and develop further new antibiotics from new derivatives must be like a treasure trove waiting to be opened by the drug discovery gurus.

If the improved productions rates can be carried forward as well, there may be hope of avoiding the apocalyptic demise of treatment options forever increasing drug-resistant infections. Whoever thought that foraging could be so productive? 

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Adele Graham-King
Contributing Editor

Adele is a design consultant who works in product development for medical and healthcare applications. Her background is in pharma, and she has a degree in applied physiology.