New starting points for antibiotics targeting P. aeruginosa FabF discovered by crystallographic fragment screening followed by hit expansion

There is an urgent need for new antibiotics. FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target. Very few inhibitors of FabF are known and most are derived from natural products. In an effort to further explore the chemical space of FabF ligands, we have carried out fragment screening by X-ray crystallography against an intermediated state-mimicking variant of P. aeruginosa FabF (PaFabF C164Q). This screen has screen resulted in 16 hits binding in or close to the malonyl-CoA or fatty acid binding site or an adjacent dimer interface. More than 80 analogues of the hit compounds have been explored making use of either commercially available or synthesised compounds. For 8 of those co-crystal structures could be determined and the most potent ligand has a binding affinity of 65 µM. This data package forms a strong foundation for the development of more potent and diverse FabF inhibitors.