Discovery of Novel Klebsiella Hits Through In-Depth Genomic Profiling, Fragment-Based Drug Design and Accumulation Assays

Annette von Delft and collaborators Nicole Stoesser, Lizbe Koekemoer, Ed Griffen, Paul Brennan, Frank von Delft, Phil Fowler, and Thomas Lanyon-Hoggat of the University of Oxford in the United Kingdom will utilize their well-established crystallographic fragment screening platform (XChem) and the newly developed Fast Forward Fragments (FFF) platform for rapidly progressing fragment hits into scaffolds, to identify novel small molecule hit series against three validated Klebsiella targets. Based on novel crystallographic fragment screening hits, they will generate novel chemical matter that directly addresses classical compound liabilities, by firstly prioritizing scaffolds that accumulate in efflux-pump expressing Klebsiella/Enterobacterales in design-make-test (DMT) cycles (assessed through a mass spectrometry based assay); secondly, by developing scaffolds by exclusively targeting resistance robust residues within the active site identified through an upfront assessment of target sequence variability; and thirdly by continuously optimizing for broad-spectrum Klebsiella spp. (plus other Enterobacterales) activity. Ultimately, they aim to enable a "ready-to-use", target-based antimicrobial discovery pipeline that can be applied to evaluating novel bacterial targets more broadly.

This grant is funded by The Novo Nordisk Foundation.