Design and Synthesis of Covalent Inhibitors of FabA

James S. Martin, Claire J. Mackenzie, De Lin, Nadine Homeyer, David W. Gray, Fabio Zuccotto, and Ian H. Gilbert

ACS Omega 2023, 8, 14, 12787–12804


There is an urgent need for the development of new therapeutics with novel modes of action to target Gram-negative bacterial infections, due to resistance to current drugs. Previously, FabA, an enzyme in the bacterial type II fatty acid biosynthesis pathway, was identified as a potential drug target in Pseudomonas aeruginosa, a Gram-negative bacteria of significant clinical concern. A chemical starting point was also identified. There is a cysteine, Cys15, in the active site of FabA, adjacent to where this compound binds. This paper describes the preparation of analogues containing an electrophilic warhead with the aim of covalent inhibition of the target. A wide variety of analogues were successfully prepared. Unfortunately, these analogues did not increase inhibition, which may be due to a loop within the enzyme partially occluding access to the cysteine.