The Discovery of Benzothiophene Derivatives as LasB Inhibitors Against Pseudomonas aeruginosa Infections

Pseudomonas aeruginosa is a clinically prevalent multidrug-resistant pathogen that poses a major therapeutic challenge. Targeting the crucial virulence factor elastase LasB has emerged as a promising strategy with which to reduce pathogenicity without imposing strong selective pressure for resistance. Here, we synthesized 19 benzoheterocyclic compounds through virtual screening and identified the benzothiophene derivative C5 as a potent LasB inhibitor (52.99 ± 0.87%). Further studies showed that C5 inhibited lasB expression in a concentration-dependent manner (IC50 = 5.80 ± 2.55 μM), thereby significantly inhibiting elastase production in Pseudomonas aeruginosa reference strain PAO1, the hypervirulent strain PA14, and the clinically resistant strains PA921 and PA929. Notably, the combination of C5 with tobramycin and ciprofloxacin significantly suppressed the development of antibiotic resistance, indicating its potential for antibacterial synergistic activity with these antibiotics. Furthermore, C5 inhibited bacterial swarming without significant cytotoxicity, demonstrating a favorable safety profile and potent activity. In summary, these results suggest that targeting LasB offers a potential strategy for treating Pseudomonas aeruginosa infections, and compound C5 has the potential to be developed as a candidate for LasB inhibitors.