Development of Diaryl Ether-based FabV Inhibitors Aimed Against P. aeruginosa

In the fight against antimicrobial resistance, one attractive yet underexplored strategy is targeting the bacterial fatty acid biosynthetic pathway (FasII). Among the most extensively studied of these targets is FabI, the most common enoyl-acyl carrier protein reductase (ENR) which catalyses the last step of the elongation cycle. Two FabI inhibitors have already reached the final stages of clinical trials. However, certain Gram-negative bacteria are resistant to FabI inhibition due to (co-)expressing the FabV isoform. Our goal is to develop potent antagonists of FabV, focusing on the WHO Priority I pathogen P. aeruginosa even though FabV is highly conserved across species. Here we present a series of diaryl ether-based binders with low micromolar affinity for paFabV derived through rational drug design