EPSRC Centre for Doctoral Training in BioDesign Engineering

Engineering microbial cell factories for production of improved anti-infectives

Lead supervisor: Prof Jason Micklefield (University of Manchester)

Co-supervisor: Dr Yi Jin (University of Manchester)

There is an urgent need for new anti-infective agents to combat antimicrobial resistance and to protect the global population in the event of future pandemics. However, existing antimicrobial drugs are becoming increasingly ineffective due to antimicrobial resistance (AMR), with microbial pathogens rapidly evolving ways to evade the effects of these drug compounds. Fungal pathogens can be particularly problematic resulting in millions of life-threatening infections every year. For example, many COVID-19 patients (particularly in India) died of a secondary infection, caused by the “black fungus” mucormycosis. Unfortunately, there are only a small number of antifungal drugs available and very few promising drug candidates in development. Moreover, the antifungals currently in use are largely ineffective against emerging multidrug-resistant fungal pathogens which pose a major threat to global health. Currently the most effective and widely used antifungals are polyene natural products such as amphotericin B (WHO essential medicine). Despite possessing good antifungal activity, polyenes exhibit significant toxicity limiting their use.

Recently, we discovered pathways including novel enzymes that produce new polyenes which have improved activity and reduced toxicity. In this project, a new synthetic biology pipeline will be developed to derivatise, optimise and scale-up production of polyene antifungals for further testing and drug development. We will develop innovative genetic approaches to engineer bacterial strains (super hosts) that can produce the best polyene derivatives in a single-step fermentation. Strains producing polyenes with optimal properties for medical use will be further engineered to boost product yields. This will include deleting competing pathways and introducing copies of genes encoding feedback resistant enzymes for precursor supply. In addition, we will explore methods to circumnavigate native regulatory control, refactoring pathways with different constitutive promoters, which can further boost product output. These cutting-edge synthetic biology approaches can provide much more sustainable, efficient, and cost-effective routes to the improved, safer and less toxic antifungal agents that we urgently need to combat the emerging drug-resistant fungal pathogens.

This project will be based at the University of Manchester.