Exploring new antimicrobial pathways using a combinatorial biosynthetic approach. (360G-Wellcome-107402_Z_15_Z)

The emergence of widespread antimicrobial resistance poses a serious threat to modern medicine and global health. To address this growing threat, I will discover new antimicrobial agents with novel modes of action using a high-throughput combinatorial biosynthetic approach. Capitalising on the power of enzymatic reactions, I will create an automated platform for engineering thousands of host cells to express different combinations of native and modified biosynthetic enzymes taken from diverse or ganisms. My research will focus on utilising enzymes involved in the biosynthesis of quinolines, a highly promising class of natural products for targeting underexploited antimicrobial pathways such as intracellular microbial communication. I will engineer and reconstitute quinoline-based pathways involved in the biosynthesis of quorum sensing molecules from P. aeruginosa and medicinal alkaloids from C. acuminata. In addition to enzymes from these two pathways, I will also incorporate divers e quinoline-modifying enzymes from completely unrelated organisms, identified through literature surveys and predictive analysis of genomic data. Combinatorial expression of these enzymes in host cells will generate thousands of new bioactive molecules inspired by quinoline natural products. I will then conduct a range of biological assays to identify the best antimicrobial candidates that display unprecedented efficacy against multidrug-resistant microbial strains.