Pathways to New Anti-infective Agents

There is an urgent need for new antibiotics. The majority of antibiotics that are used to treat infectious diseases today are small molecules produced by microorganisms, called natural products, or derivatives thereof. The existing antibiotics have become less effective as pathogens evolve resistance to these molecules. Consequently, we need to discover new antibiotics and also develop methods to diversify/optimise the structure of these molecules if we are to combat emerging antimicrobial resistance (AMR). In this project, we aim to use state-of-the-art synthetic biology technologies, including CRISPR-cas9 gene editing and directed evolution, to create new enzymes and pathways that deliver novel antibiotics. We will focus on hybrid nonribosomal peptide and polyketide natural products that show promising antimicrobial activity. Initially we will characterise the key enzymes required for the biosynthesis of these natural products, including non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) assembly line enzymes, as well as the tailoring enzymes that introduce functionality that is essential for activity. We will then use this knowledge to guide engineering of NRPS/PKS enzymes that accept alternative substrates and evolve new tailoring enzymes to derivatise and further diversify the antibiotic scaffolds. Also, in light of the recent pandemic, several novel anti-viral target compounds have been identified which have potential to inhibit replication of SARS-Cov-2. Enzymatic pathways to these anti-viral molecules will also be explored.