Extending the power of structure-guided fragment-based drug discovery (FBDD)

The aims of this project are to extend the power of structure-guided fragment-based drug discovery (FBDD) to develop rapid, robust, and effective methods to create antibiotics against Mycobacterium abscessus. I will therefore: 1. Optimise chemical scaffold-target selection, by (i) phenotypic screening of hit-finding fragment libraries created using diversity oriented synthesis, and then (ii) identifying targets through photochemical cross-linking, whole cell thermal shift assay, whole genome sequencing of escape mutants, and screening against existing arrayed inducible CRISPR-dCas9 hypomorphs; 2. Define the chemical rules for bacterial permeation, retention, and metabolism, using machine-learning cheminformatic analysis of LC-MS-based compound screening; and 3. Exploit these new datasets for optimising drug target and chemical selection, binding site exploitation, and chemical elaboration to (i) pursue a fragment-based drug discovery campaign (guided by X-ray crystallography) and (ii) implement ultra-large in silico screening of make-on demand compounds to deliver instant antimicrobial drug-like molecules.