Exploring the Structure-Activity-Relationship of the ‘B’-ring in Diaryl Ether-Based paFabV Inhibitors

The uncontrolled rise and spread of antimicrobial resistance (AMR) is one of the most severe and immediate threats to global health. Resistant infections are responsible for millions of deaths worldwide annually and current trends indicate that the issue will only aggravate in the future. Meanwhile, commercial drug development is dominated by incremental modifications of existing intellectual property instead of exploring novel therapeutic strategies with lower likelihood of resistance development. FabV is an enoyl acyl carrier protein reductase (ENR), 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 along with its more frequently occurring isozyme FabI, and is therefore resistant to common FabI inhibitors. This study sought to investigate the rational, iterative design of paFabV inhibitors. A total of 44 compounds, based on the existing diaryl ether scaffold for ENR inhibition, were synthesized and screened in an enzymatic assay. This resulted in a potent inhibitor of FabV, RGB32, with an IC50 value of 0.59 ± 0.04 μM. The results of this work could serve as an encouraging starting point for further investigation of the therapeutic potential of FabV inhibition.