Work

Kinetic Target-Guided Discovery of Selective Nanomolar Hydroxamic Acid–Based Inhibitors of Pseudomonas aeruginosa Elastase LasB

Year: 2026

Type: preprint

Abstract: Antimicrobial resistance is increasingly becoming a critical threat to human health. Pseudomonas aeruginosa is classified as a high-priority pathogen, and treating it with traditional antibiotics is increasingly challenging. In this work, we report on a non-traditional approach: targeting Elastase B, a major virulence factor that drives P. aeruginosa pathogenicity. Guided by prior crystallographic data, we employed a kinetic target-guided synthesis (KTGS) approach followed by an extensive structure–activity relationship (SAR) study, leading to the identification of inhibitors with single-digit nanomolar inhibitory potency (IC50= 1.7 ± 0.1 nM). These compounds also displayed excellent selectivity against a panel of human off-targets, protected lung epithelial cells from LasB-associated damage, and showed encouraging in vivo efficacy. Moreover, pulmonary pharmacokinetic studies revealed ELF and lung exposure above the biochemical IC50 values, supporting their further development as antivirulence agents against P. aeruginosa lung infections.

Source: ChemRxiv

DOI: 10.26434/chemrxiv.15010074/v1