A novel way of synthesising a promising new antibiotic has been identified by scientists at the University of Bristol. By expressing the genes involved in the production of pleuromutilin in a different type of fungus, the researchers have been able to increase production by more than 2000%.
CDC/Melissa Dankel; James Gathany.jpg
With resistance growing to existing antibiotics, there is a vital and urgent need for the discovery and development of new antibiotics that are cost-effective. Promising developments are derivatives of the antibiotic pleuromutilin, isolated from the mushroom Clitopilus passeckerianus.
These new compounds are some of the only new classes of antibiotic to join the market recently as human therapeutics. Furthermore, with their novel mode of action and lack of cross-resistance, pleuromutilins and their derivatives represent a class with further great potential, particularly for treating resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and extensively drug resistant tuberculosis (XTB).
However, mushrooms are basidiomycete fungi which are not generally amenable to strain improvement and fermentation. Therefore, in collaboration with pharmaceutical company GSK, Bristol scientists carried out research to identify the genes involved in the production of pleuromutilin. They discovered that a seven-gene cluster is required to produce the antibiotic in C. passeckerianus. The seven-gene pleuromutilin cluster was then reconstructed within a more industrial fungus, Aspergillus oryzae, which belongs to a different group of fungi, the ascomycetes. This resulted in a significant increase (2106%) in production.
This is the first gene cluster from a basidiomycete to be expressed successfully in an ascomycete, and paves the way for the exploitation of a metabolically rich but traditionally overlooked group of fungi. The research was published recently in the journal Scientific Reports (Bailey AM, Alberti F, Kilaru S et al. Identification and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased rapid antibiotic production. Sci Rep 2016; 6: 25202).