Investigating the structure-activity-relationship of diaryl ether-based paFabV inhibitors: A path to novel antibacterials.

The uncontrolled rise and spread of antimicrobial resistance (AMR) is a critical and immediate threat to global health, responsible for millions of deaths annually, with current trends indicating that the global burden of disease is poised to increase dramatically in the coming decades. Meanwhile, the antibiotic pipeline is dominated by incremental variations on compounds already in clinical use. There is thus a pressing need to explore novel therapeutic strategies with lower likelihood of resistance development. One such promising target is FabV, an enoyl-acyl carrier protein reductase (ENR). These enzymes represent a crucial component of the universal bacterial fatty acid biosynthetic pathway (FasII), that is found across several critical Gram-negative bacteria. This includes P. aeruginosa, an opportunistic pathogen associated with hospital infections. This pathogen co-expresses FabV with its more common isozyme FabI, rendering it resistant to existing FabI inhibitors. This study aimed to investigate the rational, iterative design of P. aeruginosa FabV (paFabV) inhibitors. A total of 59 compounds, based on the previously established diaryl ether scaffold for ENR inhibition, were synthesized and screened in an NADH absorbance-based enzymatic assay. These efforts resulted in identifying para-benzenesulfonamides as privileged motifs and establishing the ideal length of the alkyl chain substituent to be five or six carbon atoms. Molecular modelling simulations indicate that the increase in potency is due to the sulfonamide group being able to engage in hydrogen bonding with Ser155, a highly conserved residue across FabV isoforms from various bacterial species. The findings reported herein provide a promising foundation for further exploration of the therapeutic potential of FabV inhibition.